Download quinolones

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CHEMO NOTES FOR FINAL
Structures to know and notes to know are highlighted in yellow.
QUINOLONES
- Synthetic antimicrobials with N-alkylated 3-carboxypyrid-4-one fused with
substituted aromatic ring.
First-Generation Quinolones
- Nalidixic acid is the first marketed quinolone in 1965. It is still available for Gram
(-) bacterial infections.
- Used for uncomplicated UT infections, mainly by E. coli.
- Other 1st generation quinolones including oxolinic acid & cinoxacin are not common
& mainly used UT disinfectants.
- They’re well absorbed orally & highly serum protein bound & hence have relatively
high t½ .
- This restricts their use to protein free compartments e.g., UT.
- Used in high doses, because of their low potency, which leads to some side
effects, e.g., GI upset, rash & visual disturbance.
- They are also proconvulsant & photosensitizers in susceptible patients.
Second-Generation Quinolones
- Not used widely till the discovery of the first fluoroquinolone norfloxacin in 1986,
which was equivalent in potency to fermentation antibiotics.
- Since the discovery of norfloxacin, thousands of 2nd-generation quinolones have
been made & marketed in the US including:
- ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, trovafloxacin,
norfloxacin, enoxacin, lomefloxacin& gatifloxacin.
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- Ciprofloxacin is completely orally absorbed, not highly protein bound.
- Lomefloxacin has comparative longer t1/2 & hence administered less frequently.
- Levofloxacin is optically active isomer of ofloxacin & nearly 2-fold more active &
more water soluble & became very popular.
- Sparfloxacin & trovafloxacin have better Gram (+) activity.
Mechanism of action
- Quinolones are bactericidal due to their inhibition of DNA gyrase& topoisomerase
IV which are key enzymes that dictate bacterial DNA conformation so that it can
be stored unwounded, replicated, repaired & transcribed when needed.
- These enzymes change the conformation of DNA by catalyzing transient double
strand cuts staggered by 4 base pairs, passing the uncut portion of the molecule
back together.
- This change DNA twisting degree & release torsional stress in the molecule.
- Inhibition of DNA gyrase & topoisomerase IV renders a cell’s DNA inaccessible,
leading to death, especially if the cell must deal with other toxic effects at the
same time.
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- Topoisomerase IV is more important to Gram (+) while DNA gyrase is important to
Gram (-) bacteria.
- Humans shape their DNA with topoisomerase II which doesn’t bind quinolones at
therapeutic doses.
- Resistance through reduced cellular uptake & mutation.
- Quinolones form chelate polyvalent with metal ions Ca2+, Mg2+, Al3+& Fe2+ to
form less water soluble complexes & hence considerably lose their potency.
- Hence, co-administration of certain antacids, hematinics, tonics & dairy products
soon after quinolones administration is contraindicated.
Side Effects
- Proconvulsant, as in 1st-generation, especially in epileptics.
- Other CNS side effects: hallucinations, insomnia, visual disturbances.
- Diarrhea, vomiting, abdominal pain & anorexia.
- Fluroquinolones are much better tolerated.
- Quinolones are associated with erosion of the load bearing joints of young animals,
hence they are not used before puberty or during pregnancy, since it can cause
severe metabolic acidosis & hemolytic anemia.
- Concomitant use with theophylline increase its effect & toxicity.
- Some fluroquinolones have narrow safety margin, e.g., temafloxacin was removed
from the market because it caused hemolysis, renal failure & thrombocytopenia.
- Recently, severe liver toxicity of trovafloxacin resulted in its removal from the
market.
- Its use is restricted to severe infections involving institutional care where liver
functions carefully monitored.
- Grepafloxacin marketed in 1997 & withdrawn in 1999 due to its cardiovascular
toxicity. It prolonged QTc interval.
- These toxicity events reduced the popularity of quinolones& apparently these side
effects were not revealed during animal & clinical studies.
Therapeutic uses
- 1st-Generation quinolones have relatively narrow anti-Gram (-) spectrum.
- 2nd-Generation quinolones are more widely used:
1. Norfloaxacin used for UT infections (enterobacter, enterococcus or P.
aeruginosa).
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2. Ciprofloxacin used for Bacillus anthrax, prostatitis, upper respiratory
tract, chronic ear & bone infections, septicemia, staphylococcus &
pseudomonal endocarditis, meningitis, sexually transmitted diseases
(gonorrhea & chlamydia) & purulent osteoarthritis.
- Anaerobes, Staph & Pseudomonas must be watched for emergence
of resistance.
3. Lomefloxacin is used once daily for UT & upper respiratory tract
infections.
- Quinolones are still under active investigation & newer agents are expected at
regular intervals.
Nitrofurans
- Oral antibacterial available since World War II.
- Used for prophylaxis & treatment of UTIs when kidney function is normal.
- It also inhibits kidney stone growth.
- It can cause nausea & vomiting which is avoided by slowing the drug’s rate of
absorption through wax-coated large particles (Macrodantin).
- It inhibits DNA & RNA functions with unknown mechanism. Resistance is not
common.
Methenamine
- Low molecular weight ammonia/formaldehyde polymer which hydrolyzes to its
components under mild acid conditions.
- The drug is used for disinfections of acid urine & recurrent UTIs.
- HCHO is the active antimicrobial component.
Phosphomycin
- Synthetic antimicrobial compound
- Inhibits enolpyruvial transferase which catalyzes early bacterial cell wall
synthesis step.
- This results in reduced synthesis of peptidoglycan & hence producing bactericidal
effect.
- Effective against E. coli & Enterobacter faecalis.
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SUMMARY
1. First-Generation Quinolones:
- Nalidixic acid, oxolinic acid & cinoxacin.
2. Second-Generation Quinolones:
- Norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin,
trovafloxacin, norfloxacin, enoxacin, lomefloxacin& gatifloxacin
3. Nitrofurans
4. Methenamine
5. Phosphomycin
Cancer Chemotherapy
- Neoplasm: New & diseased form of tissue growth.
- The difference between benign & malignant tumors is the latter can metastasize.
- So benign tumors can be removed surgically since they have defined borders.
- Malignant tumors are invasive to surrounding tissue & their complete removal is
difficult.
- They form secondary tumors at locations distant from that of primary tumors.
- So malignant tumor cells of primary tumor can be shed & distributed by the
vascular or lymph system to other places.
- Hence, Cancer spreads by metastasis: ability to penetrate lymphatic & blood
vessels, circulate through the bloodstream & then invade & grow in normal body
tissues somewhere else, which makes cancer a potentially life-threatening disease
- Metastasis requires the growth of a new network of blood vessels.
- Angiogenesis is the recruitment of new blood vessels.
- Tumor angiogenesis is the proliferation of a network of blood vessels that
penetrates into cancerous growths, supplying nutrients, oxygen & removing waste
products.
- Angiogenesis is directly related to metastasis.
- The highly vascular primary tumors having a higher incidence of metastasis than
poorly vascular tumors.
- Shedding of cells from the primary tumor begins only after the tumor has a full
network of blood vessels.
- Beside cancer, pathological angiogenesis also occurs in chronic inflammation, or
atherosclerosis vessels
- Normal Angiogenesis occurs during wound healing, new blood vessels are formed
during tissue growth & repair & the development of the fetus during pregnancy
Angiogenesis
- In a mother’s womb, human fetus must create the vast network of arteries, veins
& capillaries through vasculogenesis, which creates the primary network of
vascular endothelial cells that will become major blood vessels
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Angiogenesis Activator
- Walls of blood vessels are formed by vascular endothelial cells which only divide
once every 3 years.
- Angiogenesis can stimulate them to divide when necessary.
- Endothelial cells are the source of new blood vessels & have the ability to divide &
migrate.
- Many proteins & small molecules are released by normal & tumor cells as signals
for angiogenesis.
- Examples for activator proteins:
- Vascular endothelial growth factor (VEGF), epidermal growth factor,
angiogenin, tumor necrosis factor-a, interleukin 8, acidic, & basic
fibroblast growth factor (bFGF).
- Examples for small molecules: Adenosine, nicotinamide, prostaglandins E1& E2
- Once VEGF & bFGF encounter endothelial cells, they bind to specific protein
receptors on the outer surface of the cells, which activates a series of relay
proteins that transmits a signal into the nucleus of the endothelial cells.
- Nuclear signal stimulates certain genes to make products needed for new
endothelial cell growth.
- Activated endothelial cells produce matrix metalloproteinases (MMPs) which are
enzymes that facilitate the degradation of the extracellular matrix.
- This permits the migration of endothelial cells into the surrounding tissues, begin
to divide & they finally organize into hollow tubes that gradually develop into a
mature network of blood vessels.
- Hence, both angiogenesis & metastasis require MMPs during blood vessel
formation & tumor invasion.
Angiogenesis Inhibitors
- Angiogenesis activators must overcome an array of natural angiogenesis inhibitors
that normally restrain blood vessel growth.
- Naturally occurring angiogenesis inhibitor proteins include:
- angiostatin, interferons, tissue inhibitors of metalloproteinase-1-3,
endostatin, platelet factor 4, interleukins 1 & 12, thrombospondin.
- The balance between the concentration of angiogenesis inhibitors & activators
decides whether a tumor can induce the growth of new blood vessels.
- Angiogenesis is predominant if production of activators exceeds production of
inhibitors.
- Angiogenesis is not only controlled by the quantity & quality of angiogenic stimuli
it also depends on the coordinated production of endogenous angiogenic &
angiostatic factors.
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- Angiogenesis may be induced by increased production of angiogenic factors or
suppressed production of angiostatic factors
- Steps required for metastasis & angiogenesis are similar for all tumors regardless
of their genetic origin, hence blocking both by inhibiting invasion is useful for all
tumors of different origin.
- The use of anti-angiogenic compounds in cancer area started to attract more
attention with the discovery of the first pro-angiogenic molecules bFGF& VEGF &
the development of in vitro methods to grow VE cells & in vivo assays of
angiogenesis.
Cell Proliferation
- Cellular life is controlled by:
1. DNA synthesis/mitosis to produce new cells &
2. Cell differentiation to produce specialized cells.
- Normal (non-transformed) cells are able to modulate/control both processes using
chemical signals as growth factors or inhibitors.
- They produce growth factors (GF) to stimulate growth & can counterbalance the
effects of GF if necessary.
- If an organ is damaged, the level of inhibitor is reduced & proliferation rate
increased.
- Cancer cells over produce GFs as epidermal growth factor (EGF) & under express
growth inhibitors as p53 or over express GF receptors.
- This lead to loss of normal growth control & increase cell proliferation.
- Control loss is possibly through transformation of proto-oncogenes, which control
normal proliferation into oncogenes which alter cellular control mechanisms.
Cell Cycle
- Gap 1 (G1) phase is the period when a newly created cell is born.
- If the cell is a proliferating cell, G1 phase will be very short & the cell will quickly
moves into the synthesis (S) phase, where DNA is replicated resulting in 2 copies of
DNA.
- Gap 2 (G2) phase is a preparation time for the final cell cycle phase M or mitosis.
- Cell cycle time is the time between mitoses.
- G1/S (when cells commit to replicate) & G2/M (when cells commit to divide)
control the cell cycle.
- During G1 phase, a cell can either enter the S phase, enter the G0 phase (Gap 0 or
quiescent) or the cell terminally differentiate & die.
- Normal cell populations may be proliferating, quiescent, or terminally
differentiating, without net change in cells number.
- Tumor cells proliferation is higher at the expense of quiescent or terminally
differentiating cells with net increase in cells number.
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- In tumors, new cells are produced in hypoxic regions which are nearer to the
tumor center & poorly perfused. These cells are usually in nonproliferative state &
not sensitive to drugs.
- After the tumor is exposed to cancer chemotherapy drug, outermost cells which
are mainly in the proliferative state are susceptible to the drug.
- Non-proliferative cells can be recruited into proliferative state.
- Hence to eradicate the tumor, several cancer chemotherapy rounds are required.
- Mutation
- Germ-line & somatic mutations
- Cells have many mechanisms for repairing damaged DNA, hence generally multiple
mutations are encountered for tumor promotion using the following sequence:
1. Initial mutation(s) (initiation)
2. Promotion, mutated cells proliferate, aided by exposure to non-genotoxic
compounds.
3. Small benign tumor forms or mild dysplasia occurs with development of
malignant phenotype.
4. Primary malignant tumor.
5. Secondary tumors (metastasis).
- Carcinogenesis is a multi-stage process that involves the initiation stage, in which
the normal cells are transformed into tumor cells.
- Initiation is irreversible & momentary reaction.
- Initiated cell can then develop into tumors with prolonged exposure to promoters
(promotion stage).
- Promoters are not carcinogenic, but rather enhance the growth &/or survival of
initiated cells.
- Example of promoters: organochlorine pesticides, estrogens, & phorbol esters
(TPA).
- Tumors can then become more highly malignant leading to the progression stage.
- Cancer chemoprevention (anti-tumor promotion) agents targets the promotion
stage unlike anti-tumor agents, which affects the progression stage.
Carcinogenic Chemicals
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- Benzo[a]pyrene (a component of soot) was the first carcinogenic chemical to be
identified.
- It is metabolized to reactive intermediates by CYP450 enzymes which react with
guanine & other DNA bases to produce single mutations.
- These mutations are either repaired or later misread when DNA is replicated
producing transitions & permanent mutations & DNA adducts.
- Other similar examples:
- b-naphthylamine, asbestos, hydrocarbons, aflatoxins, tobacco smoke &
alkylating agents.
- Ionizing radiation produce reactive oxygen species (ROS) as hydroxy radical which
produce DNA adduct & single or double strand DNA damage.
Cancer Therapy
1. Surgery
- Cancer must be in 1ry tumor stage to make sure the entire tumor will be
excised & without causing excessive damage to vital organs.
2. Radiation Therapy
- Used to shrink or destroy tumors by damaging DNA of tumor cells. X-ray
radiation is used without anesthesia. Tumor must be localized for
successful therapy.
3. Immunologic Therapy
- Administration of interferons, mainly interferon-2 stimulate immune
system to eradicate cancer by boosting the levels of lymphocytes,
especially Tcells (destroy foreign malignant & premalignant cells) & B-cells
(make antibodies in response to foreign protein expressed by cancer cells).
4. Chemotherapy
- Mainly targets the cure of a specific cancer type, reduce tumor size
before surgery, sensitizing tumors to radiation therapy or destroy
microscopic metastases after tumor surgical removal.
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- Chemotherapeutic agents are complementary to either surgery or radiation
therapy for metastasized or residual tumors.
- They are effective for small tumors because large tumors are not well perfused
by blood & hence inner part of tumors is not accessible to drugs.
- Chemotherapeutic agents are basically cytotoxic & can kill both malignant &
normal cells. Their selectivity is mainly rely on the faster proliferation rate &
extracellular material uptake by malignant cells.
- However, few normal cells are rapidly proliferating, e.g., hair, bone marrow & GIT
cell lining cells.
- Hence cancer chemotherapy usually causes hair loss, immune system depression,
nausea or diarrhea.
- These side effects usually disappear once chemotherapy is discontinued.
- Early cancer detection is essential for cancer therapy success since tumor are
likely to be small without secondary tumors.
- Complete remission rate of testicular cancer & Hodgkins disease is 80-85% with
5-year survival rate.
- Other cancer types could have lower remission rates like lung cancer (15%), liver &
pancreas cancers (10% or less 5-year survival rates).
Anticancer Drugs:
1. Alkylating Agents
2. Antimetabolityes& Nucleoside Analogs
3. Antitumor Antibiotics
4. Antimitotic Agents
5. Miscellaneous Agents
6. Antiangiogenic Drugs
7. Hormonal Therapy
1. Alkylating Agents
- The use of sulfur mustard in World War I revealed that tissues of victims were
damaged at sites distant from contact area.
- This included: leukopenia, bone marrow aplasia, lymphoid tissue suppression & GIT
ulceration.
- Sulfur mustard has too nonspecific anti-tumor effect in animals.
- Nitrogen mustards were later synthesized, e.g., mechlorethamine, which has
better selective toxicity especially to lymphoid tissue.
- Mechlorethamine was then used successfully for Hodgkin’s disease & certain
lymphomas.
- Alkylation is the replacement of H by an alkyl group. Alkylation of nucleic acids or
proteins includes a substitution reaction in which a nucleophilic atom (nu) of the
biopolymer replaces a leaving group from alkylating agent.
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nu-H + alkyl-Y alkyl-nu + H+ + Y
Alkylating agents are classified into:
1. Nitrogen mustards
- The oldest example is mechlorethamine, approved by FDA in 1949.
- Other related compounds include:
- cyclophosphamide, ifosfamide, chlorambucil, estramustine
phosphate & melphalan.
- They react with DNA through heterocyclic mechanisms.
2. Thiotepa & busulfan
3. Nitrosoureas, e.g., carmustine& lomustine.
- Alkylating agents act by alkylation of DNA, mostly at N-7 position of guanine. Other DNA bases, e.g., adenine, thymine or cytosine or DNA backbone phosphate
oxygens may also be alkylated.
- Difunctional alkylating agents as mustards may alkylate 2 DNA sites, producing
intra- or interstrand links.
- Alkylated DNA site becomes liable to cleavage resulting in single strand breaks of
nuclear DNA.
- Alkylating agents react with DNA & RNA & proteins.
- Bifunctional alkylating agents can produce inter & intra-strand cross-links.
- Inter-strand links formed by mechlorethamine aziridinium ions prevent DNA
separation & cause cytotoxicity.
- Reaction with N-7 of guanine is highly favorable.
- Alkylating agents are effective in G1 or S phase.
- DNA alkylation repair could occur where an endonuclease cuts the damaged strand
& the region is backfilled.
- Rapidly proliferating agents have insufficient time to repair.
- Hence, alkylating agents should be most effective against rapidly proliferating
cells, & hence, somewhat selective to cancer cells.
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- Despite Cl atom, which is the leaving group in the mustards is not an easily
replacable atom, the nitrogen atom in mustards activates the chloride by
proceeding through an aziridinum ion intermediate.
- Hence, nitrogen mustards are very reactive agents & must be administered
intravenously.
I. Nitrogen Mustards
1. Mechlorethamine (Mustargen)
- Simplest nitrogen mustards.
- Aqueous injectable formulations of mechlorethamine HCl salt (pH 3-5) are
triturated with NaCl at a conc. of 1mg/ml.
- In vivo hydrolysis of mechlorethamine is rapid (t1/2 ~15 min.) & the active drug
form lasts for few minutes only.
- Used intravenously or intracavitary (10mg/vial) for lung carcinoma, chronic
lymphocytic leukemia (CLL), Hodgkin’s lymphoma lymphosarcoma, chronic myelocytic
leukemia.
- Toxicity
- Bone marrow depression
2. Melphalan (Alkeran, L-PAM, L-Phenylalanine Mustard)
- Chemically related to the natural phenylalanine amino acid.
- The L-isomer is transported preferentially with the assistance of an L-amino acid
active transporter.
- D-Phenylalanine mustards require a higher dose to reach the same cytotoxicity
level against animal tumors than the marketed L-enantiomer.
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- ~30% of administered dose is accounted for covalently bound form with plasma
protein.
- Used orally as 2 mg tablets or intravenously (50mg/vial).
- Effective against ovarian carcinoma & multiple myeloma
- Toxicity:
- mainly bone marrow depression.
3. Cyclophosphamide (Cytoxan)
- Despite it is chemically related to nitrogen mustards, its mustard nitrogen
nucleophilicity is tremendously reduced with the amide-like phosphoramide linkage.
- Hence, it is less likely to form aziridinium ion, compared with nitrogen mustards.
- This increased its chemical stability.
- Cyclophosphamide contains several polarizable groups which improve its H2O
solubility.
- Cyclophosphamide is a pro-drug that requires metabolic bioactivation started with
cytochrome P450 hydroxylation to an unstable carbinolamine intermediate, which
fragment to acrolein & phosphoramide mustard, an active alkylating agent.
- Phosphoramide mustard forms an aziridinum analog which is an effective DNA
cross-linking & cytotoxic agent.
- Cyclophosphamide is well absorbed orally as tablets (25 & 50 mg).
- It is also available as iv injections (100, 200, 500 & 1000 mg/vial).
- It is used for:
- breast & ovary carcinomas, all acute monocytic leukemia, acute myelogenous
leukemia, Hodgkin’s & non-Hodgkin’s lymphoma, mutiple myeloma,
neuroblastoma & retinoblastoma.
- Toxicity: bone marrow depression, hemorrhagic cystitis (acrolein metabolite)
4. Ifosphamide (Ifex)
- Analogue of cyclophosphamide.
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- Metabolic activation by CYP450 is required for the cytotoxic activity.
- Similar to cyclophosphamide, hydroxylation at C-4 produces the active unstable
carbinolamine metabolite, 4-hydroxyifosphamide, which degrades to additional
cytotoxic metabolite.
- Used for testicular carcinoma as iv or intracavitary injections, 1000mg &
3000mg/vial.
- Toxicity: bone marrow depression & hemorrhagic cystitis (caused by acrolein
metabolite).
- 2-Mercaptoethanesulfonate (MESNA, Mesenex) is an anticancer adjunct coadministered with cyclophosphamide or ifosphamide to conjugate their toxic
acrolein metabolites, which reduces the hemorrhagic cystitis & nephron &
urotoxicities induced by these toxic metabolites.
5. Chlorambucil (Leukeran)
- Original nitrogen mustard in which an alternative approach was used to
reduce the reactivity of alkyl nitrogen mustards by attaching an aromatic group to
them.
- This decreases the basicity & nucleophilicity of the mustard nitrogen.
- Well absorbed orally & metabolized in vivo into another active metabolite,
phenylacetic acid mustard.
- This 2-carbon loss from butanoic acid side-chain is reminiscent of a fatty acid
metabolism pathway.
- Both chlorambucil& its metabolite are highly protein-bound, like any acidic
compounds.
- Used orally as 2mg tablets for chronic lymphocytic leukemia, Hodgkin’s & nonHodgkins’lymphoma.
- Toxicity: bone marrow depression
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6. Estramustine Phosphate (Emcyt)
- An estradiol analog with phosphoric acid at C-17 & carabmoylated at C-3
with a nitrogen mustard analogue.
- Formulated as di-sodium salt imparted by the phosphate ester. Freely water
soluble.
- Alkylating moiety is not a true mustard as the N is acylated as part of the
carbamate ester.
- After oral administration, estramustine phosphate is rapidly dephosphorylated.
- The major metabolites are free estramustine, estrone& estradiol.
- Used orally as 140 mg capsules specifically for prostate carcinoma.
- Toxicity:
- Gynecomastia, nausea & vomiting.
II. Other Alkylating Agents
1. Busulfan (Myleran)
- Sulfonic acid ester that is an electrophile with methane sulfonic acid acting as a
leaving group.
- Hydrolysis or alkylation reactions are the major metabolic pathways of busulfan
- Determination of 3-hydroxytetrahydrothiophene- 1,1-dioxide as the major urinary
metabolite in animals suggested the electrophilic reactivity of busulfan is due to
SH groups in the body.
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- Busulfan is a neutral molecule & poorly water soluble.
- Used as 2mg tablets for chronic myelocytic leukemia.
- Toxicity include bone marrow depression & pneumonitis/pulmonary fibrosis.
2. Thiotepa (Thioplex)
- Less reactive drug with 3 aziridine (
) moieties, which react with nucleophiles
to relieve ring strains.
- At acidic pH, aziridine group is protonated to give reactive aziridinium
ion which is known to alkylate DNA.
- At physiologic pH, aziridine with a pKa ~6, is mainly in the free base form which is
less reactive alkylating species.
- Metabolic desulfuration of thiotepa give a toxic metabolite, TEPA
(triethylenephosphoramide).
- The drug is used as iv, intravesically & intracavitar injections, 15 mg/vial for
breast, bladder & ovary carcinomas, Hodgkin’s & non-Hodgkin’s lymphoma, malignant
effusions & lymphosarcoma.
- Toxicity: Bone marrow depression.
3. Procarbazine (Matulane)
- DNA alkylation can be achieved by free radical intermediates. This can be done
using substituted hydrazines which produce radical intermediate in vitro.
- Procarbazine is an example for this case.
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- At physiologic pH, in presence of O2, procarbazine decomposes by autooxidation,
releasing H2O2.
- The formed azo derivative is further hydrolyzed to a benzaldehyde analog &
methylhydrazine.
- Methylhydrazine is oxidized to methyldiazene & then to a methyl radical, which
methylate DNA guanine at C-8.
- The benzaldehyde derivative is excreted in urine after oxidation to an acid.
- Procarbazine inhibits alcohol & catecholamine metabolic enzymes, producing
Antabuse (disulfuram)-like effect with alcohol intake.
- Monoamine oxidase is also inhibited by procarbazine.
- Hence, drug interactions with sympathomimetics drugs, tricyclic antidepressants
& tyramine-containing food are expected.
- The drug is used orally as capsules (50 mg each) for Hodgkin’s lymphoma.
- Toxicity: Bone marrow depression
4. Dacarbazine (DTIC-Dome) & Temozolomide (Temnodal)
- Dacarbazine is metabolically activated through series of reactions involving
CYP450.
- Initial demethylation to MTIC followed by formation of diazomethane, a potent
methylating agent which methylate N-7 of DNA guanine.
- The major urine metabolite is 5-aminoimidazole-4-carboxyamide, which supports
the proposed mechanism.
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- Temozolomide is a pro-drug which is non-enzymatically converted to MTIC (Ndemethyl dacarbazine), which then alkylate DNA similar to DTIC.
- It is recently approved by the FDA for brain tumors.
- Unlike DTIC, which must be administered intravenously, temozolomide is
administered & rapidly absorbed orally, which is an advantage over DTIC.
- Used orally as a 5, 20, 100 & 250 mg capsules. Common side effects include bone
marrow depression, nausea, vomiting, constipation, headache & fatigue.
III. Nitrosoureas
- These compounds produce reactive alkylating vinyl cations& isocyanate species by
reactions with water.
- In water, urea NH is deprotonated & negatively charged oxygen displaces Cl
to give the cyclic oxazolidine.
- This intermediate fragments to vinyl diazohydroxide& 2-chloroethylisocyanate.
- Both are reactive alkylating species & give the very reactive vinyl cation& 2chloroethylamine.
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1. Carmustine (BiCNU, 1,3-bis(chloroethyl)-1-nitrosourea,)
- Neutral molecule, highly lipophilic, H2O insoluble which allow efficient crossing of
blood-brain barrier& provide higher CSF/plasma ratios, compared with other
alkylating agents.
- Alkylate DNA & RNA though no cross resistance with nitrogen mustards.
- Enzyme inhibition by carbamoylation of proteins have been suggested as an
alternate mechanism of anti-neoplastic activity.
- Rapidly metabolized after iv injection to form active metabolites.
- Carmustine is a low melting solid, as it decomposes, its melting point drops such
that partially degraded preparations may be in liquid forms at room temperature.
- Vials of carmustine that show an oily film indicate that the drug has decomposed
& these vials should not be used.
- Carmustine is administered as a 10% aqueous ethanolic solution for iv use (100
mg/vial) for Hodgkin’s & non-Hodgkin’s lymphoma, multiple myeloma, primary brain
tumor.
- The main side effect includes bone marrow depression.
2. Lomustine (CeeNU, CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)
- Similar to carmustine in solubility & activity.
- Used orally as capsules (10, 40 & 100 mg) for Hodgkin’s lymphoma, primary &
metastatic brain tumors.
- Toxicity: bone marrow depression.
3. Streptozocin (Zanosar)
- Combination of amino sugar& nitrosourea.
- The sugar moiety improves water solubility (compared with other anti-neoplastic
nitrosoureas)& it exists in both a & b-anomeric forms.
- Inhibits DNA synthesis & cell proliferation
- It also induces diabetes-like syndrome in animals.
- This is mediated by lowering of -cell concentrations of NAD.
- Indicated as iv injections (1000 mg/vial) for pancreatic carcinoma.
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- The main side effect is renal damage.
4. Cisplatin (Platinol)
- Platinum complex containing 2 NH3 molecules & 2 Cl atoms in cis configuration.
- It is nominally soluble in water or saline at 1mg/ml.
- Reactivity with cellular nucleophiles or H2O is much faster than its metabolic
reactions.
- Injectable formulation is at a concentration near its solubility in saline & it should
not be refrigerated because it will precipitate out.
- After administration, most platinum becomes tightly bound to plasma proteins
including albumin, transferring & g-globulin.
- Dose must be carefully administered because even hemodialysis after 4-hours of
administration will have little effect in cases of overdoses because of its tight
protein binding.
- Pt is detectable in tissue even after 180 days after the last dose.
- Needles or intravenous sets containing aluminium parts should never be used
because cisplatin reacts with Al resulting in a precipitate & loss of activity.
- The effect of cisplatin is associated with its ability to alkylate N-7 of DNA
guanine, forming intrastrand & interstrand cross links.
- Use as iv injections (1mg/ml, 50 & 100 ml) particularly for bladder, ovary & testes
carcinoma.
- Toxicity: Renal damage
5. Carboplatin (Paraplatin)
- Similar to cisplatin in containing cis-diammine group & platinum (II)
with organometallic cyclobutane replacing 2Cl groups in cisplatin.
- Carboplatin is soluble in water (14 mg/ml) & hence can be used as iv injections (50,
150 & 450 mg/vial).
- It is insoluble in organic solvents as ethanol & acetone.
- Replacement of Cl with water in carboplatin forms a monohydroxy derivative
which retain the anticancer activity with slower reaction rate, which justify why
carboplatin is less potent than cisplatin.
- Used for ovaries carcinoma
- Toxicity: bone marrow depression.
CHEMO FINAL Page 21 of 46
SUMMARY
Alkylating Agents:
I. Nitrogen Mustards:
- Mechlorethamine, melphalan, cyclophosphamide, ifosphamide,
chlorambucil & estramustine
II. Other Alkylating Agents:
- Busulfan, thiotepa, procarbazine, dacarbazine & temozolomide
III. Nitrosoureas:
- Carmustine, lomustine, streptozocin, cisplatin & carboplatin
2. Antimetabolites & Nucleoside Analogs
- Antimetabolites are compounds that competitively inhibit the biosynthesis of
normal cellular metabolites usually due to close structure similarity between
antimetabolites & natural metabolites.
- The well known examples are methotrexate & 5-fluorouracil (5-FU), the suicidesubstrate enzyme inhibitor.
Antimetabolites:
I. Pyrimidine antimetabolites:
- 5FU, cytarabine (Ara-C), Gemcitabine
II. Purine antimetabolites:
- 6-Mercaptopurine, 6-Thioguanine, Fludarabine & cladribine
III. Other antimetabolites:
- Methotrexate
I. Pyrimidine antimetabolites:
1. 5-Fluorouracil (5-FU, Adrucil)
- Substituted pyrimidine analog, one of the oldest antimetabolites, designed by
Heidelberger in 1957.
- Some tumors preferentially use uracil rather than using orotic acid for the
biosynthesis of DNA pyrimidines.
- Thymidine synthesis from uracil involves thymidylate synthetase
- A thiol group of a cysteine residue in the enzyme (E-SH) adds to the C-6 position
of deoxyuridylic acid with subsequent addition of C-5 carbon to the N-5,N-10methylene tetrahydrofolate.
CHEMO FINAL Page 22 of 46
- The resulting intermediate transfers the C-5 H to folate N-10 to give
deoxythymidylic acid, dihydrofolate& regenerated enzyme.
- 5-FU must be first activated in vivo by conversion to 5-fluoro-2’-deoxyuridine
monophosphate (5-FdUMP) through formation of 5FU riboside which is then
transformed into 5-FdUMP catalyzed by ribonucleotide reductase.
- 5-FdUMP binds to thymidylate synthetase to give an intermediate similar to that
of uridylic acid but with C-5 F atom instead of H.
CHEMO FINAL Page 23 of 46
- Hence the enzyme is inhibited because this intermediate will not be able to break
down to give deoxythymidine monophosphate (dTMP).
- The overall result is a deficiency in thymidine which is essential for DNA
synthesis.
- 5-FU can also be metabolized & reduced by dihydropyrimidine dehydrogenase
which give the inactive 5-F-5,6-dihydrouracil.
- This enzyme can be inhibited by 5-ethynyluracil, which doubles the therapeutic
index of 5-FU by 2-4 folds.
- 5-FU is used (iv, 500 mg/vial or topically 1-5%) for breast, colon, rectum, skin,
pancreas & stomach carcinoma.
- Toxicity: bone marrow depression & oral/GI ulceration.
- Remember: The antifungal flucytosine: 2- 5-Fluorodeoxyuridine (floxuridine,
FUDR)
2. 5-Fluorodeoxyuridine (floxuridine, FUDR)
- Prodrug of 5-FU, which can be used alternatively.
- Deoxyribose rapidly cleaved metabolically to give 5FU.
- Floxuridine is freely water soluble unlike 5-FU.
- Used intra-arterially (500 mg/vial) as a palliative therapy of GI adenocarcinoma
metastatic to liver.
- Toxicity: similar to 5-FU
3. Cytarabine (Ara-C, Cytosar-U)
- Pyrimidine nucleoside with arabinose (C-2’ b-OH & not a as in 5FUR).
CHEMO FINAL Page 24 of 46
- The change in the C-2’ configuration results in a notable broadening of the
activity spectrum.
- Similar to 5FU, Ara-C has to be converted to its mono- followed by
triphosphate derivative (Ara-CTP).
- Ara-CTP inhibits the conversion of cytidylic acid to 2’-deoxycytidylic acid.
- It also inhibits DNA dependant DNA polymerase.
- Ara-C causes miscoding after its incorporation into DNA & RNA.
- It is rapidly metabolized (oxidative deamination) into the inactive
arabinofuranosyluracil.
- Ara-C is water soluble, used as iv, intrathecal or subcutaneous injections (20, 50,
100 mg/100ml) for acute lymphocytic leukemia, meningeal leukemia, acute
myelogenous leukemia, chronic myelocytic leukemia.
- Toxicity: bone marrow depression.
4. Gemcitabine (Gemzar)
CHEMO FINAL Page 25 of 46
- Recent C-2’ difluoro pyrimidine analog.
- Unlike Ara-C, it shows excellent activity against murine solid tumors.
- It has to be bioactivated to the active triphosphate metabolite which then
incorporated into DNA causing cell toxicity.
- The drug incorporates into RNA & inhibits both DNA & RNA synthesis.
- Active against locally advanced or metastatic pancreatic adenocarcinoma, human
T-lymphoblastoids & human chronic myelogenous leukemia.
- Used intravenously (200 & 1000 mg/vial).
- Extensively metabolized into the inactive metabolite 2’-deoxy-2’,2’ -diflurouridine
(dFdU).
II. Purine antimetabolites
1. 6-Mercaptopurine (Purinethol, 6-MP)
- 6-MP is bioactivated in vivo to the corresponding ribouncleotide, 6-thioinosinate
(6-MPMP), catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
6-MPMP is a potent inhibitor of the conversion of 5-phosphoribosyl pyrophosphate
into 5-phosphoribosylamine, which is the first step in purine biosynthesis.
- 6-Thioinosinate also inhibits the conversion of inosinic acid to xanthylic acid.
- The overall effect of 6-MP is the inhibition of purine biosynthesis.
CHEMO FINAL Page 26 of 46
Cellular Targets of 6-MP
- 6-Thioinosinate di & triphosphate anabolites further inhibit biosynthesis &
incorporation of guanine in DNA & RNA chains, hence inhibiting chain elongation.
- 6-Thioinosinate can also be a substrate for adenosylmethionine, converted to 6methylthioinosinate, which also have antimetabolic activity.
- 6-MP is orally active as 50 mg tablets although its oral absorption erratic.
- Urinary metabolites include thiouric acid, formed by xanthine oxidase & many
methylthiopurines.
- Concurrent administration of mercaptopurine with uricosouric xanthine oxidase
inhibitors like allopurinol requires dose adjustment of mercaptopurine.
- Cross resistance with other purine drugs, e.g., thioguanine is expected.
- Used for acute lymphocytic, myelomonocytic & myelogenous leukemia.
- Toxicity: Bone marrow depression
2. 6-Thioguanine (6-TG)
- An antimetabolite structurally related to 6-MP.
- Similar to MP, it has to be ribosylated catalyzed by HPGRT to monophosphate (6TGMP), diphosphate (6-TGDP) & triphosphate (6-TGTP).
- Each of these anabolites inhibit several enzymes similar to 6-MP.
- Also 6-TGTP can be incorporated into RNA or into DNA after reduction of C-2’
OH.
- This inhibits DNA replication due to the inability of replication enzymes to
recognize 6-TG.
- Activity margin & toxicity are comparable with 6-MP but 6-TG deactivation is not
dependant on xanthine oxidase which is an advantage over 6-MP.
CHEMO FINAL Page 27 of 46
3. Fludarabine Phosphate (Fludara) & Cladribine (Leustatin)
- Structurally related antimetabolites to adenine with modified sugars.
- Fludarabine is a derivative of the Antiviral & antimetabolite Ara-A
(adenosine 2’-b-anomer).
- Fludarabine is more effective than vidarabine because it is less susceptible to
adenosine deaminase.
- It is converted in vivo to its 5’-triphosphate which is inhibitor of ribonucleotide
reductase.
- Cladribine (2-chloro analogue) mainly inhibits DNA repair enzymes.
- Fludarabine is used for chronic lymphocytic leukemia while cladribine is useful
against hairy–cell leukemia.
- They both can cause bone marrow depression & used intravenously 10-50 mg/vial
III. Other antimetabolites
Methotrexate (Folex, MTX)
- Pteridine analog that compete with normal folic avid & dihydrofolate substrates
for the active site on dihydrofolate reductase (DHFR).
- DHFR is responsible for the reduction of folic acid (FA) to dihydro FA & then to
tetrahydroFA, which is essential for the next round of uridylic to thymidylic acids
biosynthesis.
- This prevents DNA synthesis & kill cells by depleting thymidylic acid.
- Hence MTX is cytotoxic due to its ability to inhibit DNA synthesis & inhibit
thymidine synthesis from uridylic acid.
- Inhibition of DHFR can also inhibit purine synthesis, since the biosynthesis of
N10-formyltetrahydrofolic acid will be inhibited. The latter is an essential formyl
(C1) donor in purine biosynthesis.
CHEMO FINAL Page 28 of 46
- N5-formyl-tetrahydrofolic acid (leucovorin) is used as “rescue” therapy to
prevent the lethal effects of methotrexate on normal cells.
- Leucovorin also inhibits active transport of methotrexate into the cells.
- MTX is metabolized in liver & intracellularly to polyglutamate forms, which
hydrolyze back to methotrexate.
- MTX is largely excreted unchanged.
- Methotrexate is indicated for Trophoblastic neoplasms, breast, head, neck &
lung carcinoma, acute & menigeal leukemia, lymphosarcoma, nonmetastatic
osteosarcoma & Burkitt’s lymphoma.
- Toxicity:
- Bone marrow depression, pneumonitis/pulmonary fibrosis & oral & GI
ulcerations.
SUMMARY:
Antimetabolites:
I. Pyrimidine antimetabolites:
- 5-FU, cytarabine (Ara-C), Gemcitabine
II. Purine antimetabolites:
- 6-Mercaptopurine, 6-Thioguanine, Fludarabine & cladribine
III. Other antimetabolites:
Methotrexate
CHEMO FINAL Page 29 of 46
3. ANTITUMOR ANTIBIOTICS
- Several microbial fermentation products that were originally rejected as
antibiotics for their toxicity have become clinically useful antitumor drugs.
1. Bleomycin (Blenoxane)
- Cytotoxic glycopeptide antibiotics discovered in 1966 from Streptomyces
verticillus.
- Current preparation is composed of a mixture of bleomycins A2& B2.
- Natural bleomycins occur as Cu chelates with ligands provided by pyrazine,
imidazole, amide & amine functional groups.
- Although Cu++ is removed during isolation, the tendency to form chelates is the
key of its cytotoxic activity.
- Bleomycins chelate in cells with Fe++. This alters the redox potential of iron &
reduce bound oxygen into reactive radical species, hydroxyl radical (OH ), which
reacts with nuclear DNA, degrading it & causing cytotoxicity.
- Bleomycins are used as intramuscular, subcutaneous, intravenous or intrapleural
injections (15-30 units/vial).
- Bleomycins are used for cervix, head, neck, penis, skin, testes carcinoma.
- It is also used for Hodgkins& non-Hodgkin’s lymphoma.
- Toxicity: Pneumonitis & pulmonary fibrosis.
2. Dactinomycin D (Actinomycin D, Cosmegen)
CHEMO FINAL Page 30 of 46
- Dactinomycins are peptide antibiotics isolated from Streptomyces parvullus.
- They consist of tricyclic phenoxazone ring in the quinone oxidation state
(3-phenoxazone-1,9-dicarboxylic acid, actinocin) & 2 identical pentapeptide lactone
appendages.
- Dactinomycin’s phenoxazone ring system is planar & can intercalate or insert into
DNA between base-pair steps.
- Intercalation of actinocin moiety needs space & hence the helix must unwind. Once inserted, actinocin moiety is held in DNA helix by p-p stacking interactions
with DNA bases.
- This causes local distortion which affects the action of topoisomerase II, which
normally regulates unwinding of coiled double-stranded DNA.
- This ultimately leads to interference with DNA replication & transcription which
causes cell death.
- Actinomycins also cause DNA cleavage by nucleases.
- Dactinomycin is light sensitive.
- It is minimally metabolized & doesn’t cross blood-brain barrier.
- It is used as intravenous injections, 0.5 mg/vial.
- The drug is used for testes carcinoma, Ewing’s sarcoma, trophoblastic& Welm’s
tumors, rhabdomycosarcoma & sarcoma botryoides.
- Toxicity:
- Bone marrow depression, stomatitis & oral/GI ulcerations.
3. Mitomycin C (Mutamycin)
- Antitumor antibiotic from Streptomyces caespitosus first discovered in 1950’s &
approved as anticancer agent in 1970’s.
- The compound is containing multiple anticancer functional groups, e.g., quinone,
aziridine & carbamate.
- The drug is a bioreductive alkylating agent.
CHEMO FINAL Page 31 of 46
- It is first bio-reductive activated then one molecule of methanol is eliminated to
give a highly reactive alkylating agent capable of mono & dialkylation (cross-linking)
of cytosine/guanine rich regions of DNA.
- Mitomycin is blue-violet crystals (due to quinone moiety.
- It is poorly absorbed in GIT & hence it must be used as iv injections (20-30
mg/vial).
- It is rapidly & extensively metabolized.
- It is specifically indicated for gastric & pancreatic carcinoma.
- Toxicity: bone marrow depression.
4. Anthracyclines
- Cytotoxic anthracycline antibiotics isolated from Streptomyces caeruleorubidus
or Streptomyces peuceticus var. caesius.
- They have tetracyclic quinone-containing ring aglycone attached to the unique
daunosamine sugar.
- Due to the presence of conjugated anthraquinone nucleus, anthracycline are
reddish in color & their administration imparts red urine coloration.
- The main problem of anthracyclines is their cardiotoxicity.
CHEMO FINAL Page 32 of 46
- Due to their molecule’s flatness, anthracyclines are able to intercalate with DNA
perpendicular to its long axis.
- The aminosugar daunosamine increases the stability of this binding through its
interaction with the DNA sugar phosphate backbone.
- This intercalation lead to a single or doublestranded DNA breaking.
- This may be the result of repair process initiated by topoisomerase.
- Anthracyclines also are able to produce reactive oxygen species as hydroxyl
radical (OH.) & superoxide radical anion (.O-O-), which damage & destroy cellular
DNA.
- Generation of these free radicals may account for anthracyclines’ cardiotoxicity.
- Recently, anthracyclines are reported to show angiogenesis inhibitory activity at a
non-toxic concentration.
- Anthracyclines are not orally active & have to be administered as iv injections (5100 mg/vial).
- Anthracyclines hydroxylated in vivo to the active daunorubinols.
- Other biotransformations include reductive cleavage of the glycosidic bond, Odemethylation, conjugation with glucouronic acid & sulfate esetrifation.
- Doxorubicin HCl (adriamycin) liposome injection (Doxil) has a smaller distribution
volume & slower clearance.
-It is used as 20 mg/vial iv injection for acute lymphoblastic& myeloplastic
leukemia, Welm’s tumor, breast, ovarian, thyroid & gastric carcinoma,
malignant lymphoma, bronchogenic carcinoma, Hodgkin’s disease, soft tissue & bone
sarcomas, neuroblastoma
- Daunorubicin (Cerubidine) is used for acute lymphocytic leukemia, acute
myelogenious leukemia & acute monocytic leukemia.
- Both doxorubicin & daunorubicin can induce bone marrow depression &
cardiotoxicity.
- Epirubicin (Ellence) has a different C-4’ configuration.
- It is much less commonly used & it is mainly used as an adjunct therapy in axillary
node tumor after resection of primary breast cancer.
- Idarubicin (idamycin) is a synthetic analog which has improved cellular uptake,
lipid solubility & hence penetrates CSF.
- It also lacks cardiotoxic side effect.
- The major metabolite of idamycin, is its 13 hydroxy derivative (idarubicinol) is
also active & has a longer t1/2 (45 hr), compared with idarubicin (22 hr).
- Idarubicin is used for acute lymphocytic& myelogeous leukemia.
CHEMO FINAL Page 33 of 46
- Toxicity: bone marrow depression
Valrubicin (Valstar)
- It is recently approved by the FDA for intravesical injection (40 mg/vial) therapy
of BCG-refractory carcinoma in situ of the urinary bladder (CIS) for which
immediate cystectomy is not an option.
5. Pentostatin (Nipent, 2’deoxycoformycin, DCF)
- Adenosine deaminase inhibitor from Streptomyces antibioticus.
- Structurally related to purines with unusual 7-membered ring
(tetrahydrodiazepine).
- Marketed as iv injections (10 mg/vial), used for a-interferon-refractory hairy-cell
leukemia in adults.
- Toxicity: bone marrow depression
6. Mitoxantrone HCl (Novantrone)
- Antitumor anthracenedione, highly conjugated, intense blue color & causes urine
blue pigmentation.
- The mechanism of action is similar to anthracyclines.
- Its acidic (pH 3-4.5) parentral preparations should not be mixed with heparin
because it can be precipitated.
- Used for acute monocytic, promyelocytic& myelogenous leukemia.
- Used as iv injections (20-30 mg/vial).
CHEMO FINAL Page 34 of 46
- Toxicity: Bone marrow depression.
4. ANTIMITOTIC AGENTS
- Drugs that prevent cellular mitosis & specially interfere with mitotic spindle
formation.
- During mitosis, the protein tubulin undergo polymerization to form the mitotic
spindle.
- Antimitotic drugs interfere with this process either by depolymerization of the
microtubules or by causing structures other than the normal mitotic spindle to
form. Lack of properly formed mitotic spindle will cause incorrect chromosomal
segregation which leads to cell death.
- Recently, the potential antiangiogenic & antimigration effects of paclitaxel&
other microtubule disruptors on tumor cells at a non-cytotoxic concentration is
reported.
- Concomitant use of paclitaxel & thalidomide in the treatment of highly vascular
colorectal tumors in mice xenograft model also showed effective decreased
expression of angiogenic growth factors.
1. Vinca Alkaloids
- First antimitotic drugs are alkaloids (vincristine & vinblastine) isolated from
periwinkle flower, Vinca rosa.
- The related semisynthetic analog vinorelbine was also introduced.
- Vinca alkaloids contain 3ry amine group which makes water soluble salts.
- They metabolized by CYP450.
- Treatment of cells with vinblastine results in the formation of 1:1 binded complex
of vinblastine & tubulin.
- Vincristine (oncovin) is used as iv vials (10mg/vial) for acute lymphocytic leukemia,
Hodgkin’s & non-Hodgkin’s lymphoma, neuroblastoma& Wilm’s tumor.
- Vinblastine (Velban) is used as iv injections (10mg/vial) for breast & testicular
carcinoma, Hodgkin’s & non-Hodgkin’s lymphoma, mycosis fungoides& Kaposi
sarcoma.
- Vinorelbine (Navelbine) is specifically indicated for non-small cell lung cancer as iv
injections (10 & 50 mg/vial).
- All vinca alkaloids cause bone marrow depression
CHEMO FINAL Page 35 of 46
2. Taxanes: Paclitaxel & Docetaxel
- Paclitaxel is natural product isolated from the Pacific yew tree in the early 1960’s
& only used & approved as anticancer in the mid 1990’s.
- Paclitaxel binds to tubulin but doesn’t cause depolymerization like Vinca alkaloids.
- Paclitaxel causes microtubules to arrange themselves in a parallel array rather
than the required arrangement of mitotic spindle, causing mitotic arrest.
- The final outcome is similar to vinca alkaloids.
- Paclitaxel is highly lipophilic, doesn’t form stable salts with acids & bases & it is
water insoluble.
- Intravenous infusion of paclitaxel is prepared a non-aqueous solution in
polyoxyethylated castor oil & dehydrated alcohol.
- Paclitaxel is hydroxylated in vivo catalyzed by CYP450 enzymes to give 6hydroxypaclitaxel, 3’-p-hydroxypaclitaxel & 6,3’-p-dihydroxypaclitaxel.
- Docetaxel is a related semisynthetic compound with different acyl moieties.
- It is formulated in polysorbate 80 & must be diluted by 13% ethanol in water
before use.
- Paclitaxel (Taxol) is used as iv injections (30 mg/5ml & 100 mg/16.7 ml) for
metastatic breast cancer & refractory metastatic ovary carcinoma.
- Docetaxel (Taxotere) is used as iv injections 920 & 80 mg/vial) for locally
advanced or metastatic breast cancer & non-small cell lung cancer.
- Both drugs can cause bone marrow depression
Antitumor antibiotics:
1. Bleomycins
2. Dactinomycin or dactinomycin D
3. Mitomycin C
4. Anthracyclines: doxorubicin, daunorubicin, idarubicin, epirubicin
5. Pentostatin
6. Mitoxantrone
Antimitotic agents
1. Vinca alkaloids: vincristine, vinblastine, vinorelbine.
2. Taxanes: Paclitaxel & docetaxel.
5. MISCELLANEOUS/NATURAL PRODUCTS
CHEMO FINAL Page 36 of 46
1. Epipodophyllotoxins
- Podophyllotoxinsare natural products obtained from the May Apple plant & were
used by Native Americans & early settlers for their GI, emetic & cathartic
effects.
- Etoposide (VePesid) & teniposide (Vumon) are semisynthetic analogs that are used
for small-scale carcinomas of lung & Hodgkin’s disease.
- Original podophyllotoxins have 1,4-cis orientation unlike the semisynthetic
etoposide & teniposide, which have 1,4-trans configuration.
- The main functional groups in etoposide (lactone, phenol, ether, acetal & glucoside)
are not salt-forming groups.
- Salts have better water solubility.
- Injections of both compounds are non-aqueous preparations & contain polysorbate
80/Tween 80, polyethylene glycol 300 & alcohol as diluents.
- They must be diluted right before administration because refrigerated solutions
may precipitate.
- Etoposide phosphate is a prodrug which quickly hydrolyzed to etoposide after iv
administration.
- Etoposide & teniposide bind to tubulin at a different site from that of vinca
alkaloids & they do not change normal microtubular structure.
- Etoposide & teniposide target G2 phase & cause protein-DNA links & DNA strand
breakage by inhibiting topoisomerase II.
- Etoposide stabilize DNA-topoisomerase II complex.
- Etoposide’s major urinary metabolites are the lactone hydrolysis products,
glucouronides & sulfate esters.
- Catechol & O-demethyl metabolites are also possible.
- Teniposide is also extinsively metabolized mainly by CYP3A4.
CHEMO FINAL Page 37 of 46
- Etoposide (VePesid) is indicated for refractory testicular cancer & small cell lung
cancer.
- It is used as iv injection (5-50 mg/vial) & as capsules (50 mg)
- Teniposide (Vumon) is specifically indicated for refractory childhood acute
lymphoblastic leukemia as non-aqueous iv injections (50 mg/5 ml diluent).
- Both drugs may cause bone marrow depression.
2. Hydroxyurea (Hydrea)
- Small neutral molecule that is well absorbed orally & excreted in urine unmetabolized.
- It acts by inhibiting ribonucleotide diphosphate reductase, causing decreased
level of deoxyribouncleotide required for DNA synthesis.
- It also chelate an Fe2+ cofactor.
- It is cell-cycle specific for the S-phase & causes cell arrest at the G1-Sinterface.
- Hence, it is useful for radiation therapy as cells in G1 phase are particularly
sensitive to radiation.
- Hydroxyurea is used orally as capsules (500 mg) for head & neck & ovarian
carcinomas, chronic myelocytic leukemia, malignant melanoma.
- Toxicity: Bone marrow depression.
3. Mitotane (Lysodren, o,p’-DDD)
- It is an adrenal cytotoxic agent chemically related to the insecticide DDT.
- Most of the drug is stored in tissue & not excreted in urine.
- Terminal plasma t1/2 18-159 days after drug discontinuations.
- It is metabolized to the polar, water-soluble phenylacetic acid metabolite through
acyl chloride intermediate.
- It is used for adrenal cortex carcinoma as 500 mg tablets.
- Toxicity: CNS depression
4. Retinoids
- Tretinoin & Alitretinon
CHEMO FINAL Page 38 of 46
- Tretinoin (all-trans retinoic acid) is a natural metabolite of vitamin A (retinol).
- It induces the differentiation of acute promyelocytic leukemia cells.
- It is well absorbed orally & highly protein-bound. CYP450 oxidative metabolism of
tretinoin give 4-oxo trans retinoic acid & its glucuronide.
- Tretinoin also isomerizes to 13 cis retinoic (isotretinoin) which is oxidized to 4oxo cis retinoic acid.
- Alitretinoin (9-cis-retinoic acid) is also a natural product which inhibits
Kaposi’s sarcoma cells by activating intracellular retinoid receptors which activate
genes which regulate cell growth, differentiation & apoptosis.
- It is also topically used for cutaneous lesions in AIDS-related Kaposi’s sarcoma.
- Topical use pose minimum toxicity.
- Its systemic use is still under investigation.
- Tretinoin (Vesanoid) is indicated as 0.1% gel for acute promyelocytic leukemia.
- Alitretinoin (Panretin) is useful as 0.1% gel for cutaneous lesions in AIDS-related
Kaposi’s sarcoma.
5. Camptothecins
- Topotecan & Irinotecan
- Topotecan HCl is a semisynthetic compound derived from the natural product
camptothecin by addition of the phenolic OH & dimethylaminoethyl groups improved
water solubility & reduced side effects without reducing the effectiveness.
- Topotecan lactone is pharmacologically active although the equilibrium between
the hydrolysis product & lactone favors the ring-opened at physiologic pH.
- Both camptothecin & topotecan are inhibitors of topoisomerase I & cause single
strand breaks in DNA which is cytotoxic.
- Irinotecan HCl is a semisynthetic piperidine analog of camptothecin.
- It is activated in vivo by hydrolysis of the carbamate functionality.
- Topotecan (Hycamtin) is indicated for ovarian metastatic carcinoma as iv
(4mg/vial) injections.
- It can cause bone marrow depression.
CHEMO FINAL Page 39 of 46
- Irinotecan (Camptosar) is used as iv injections (100 mg/5ml) for colon or rectum
metastatic carcinoma.
- Toxicity: late diarrhea.
6. Porfimer Sodium
- Photosensitizing agent used in photodynamic therapy (PDT) of tumors.
- It is an oligomeric mixture of up to 8 porphyrin units linked together by ester &
ether linkages.
- It is dark red color.
- It is cleared from tissues other than tumors, e.g., skin, reticuloendothelial system
tissues quickly.
- After the drug accumulates in tumor tissue, tumor is illuminated with a laser at l
630 nm.
- Laser light promotes the porfimer polymer to an excited state which initiates &
propagates radical reactions.
- Single oxygen (O•), superoxide anion (•O-O) & hydroxyl radical (OH•) formed in
the reaction by spin transfer from profimer polymer to molecular oxygen.
- Patients experience photosensitivity for ~30 days & cautioned to avoid skin & eyes
exposure to direct sun light or bright indoor light.
- Visible light causes photoactivation, hence UV sunscreens are of no value against
porfimer photosensitivity.
6. HORMONAL THERAPY
- Hormonal therapy is common specially in breast cancers with antiestrogens &
prostate cancer with gonadotropin-releasing hormone (GnRH) agonists &
antiandrogens.
1. Antiestrogens
- Tamoxifen & toremifene are prototype antiestrogens with a complex
mechanism not limited to its antiestrogenic activity; for breast cancer
- Tamoxifen (Novaldex) is used orally as tablets (10 & 20 mg) for breast cancer.
- Toxicity: Hot flashes, nausea & vomiting.
- Toremifene (Fareston) is also used orally for breast cancer as tablets (88.5
mg/tab) & it has a similar toxicity profile as tamoxifen.
CHEMO FINAL Page 40 of 46
- Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy.
Buzdar, Aman U.; Hortobagyi, Gabriel N. Dep. Beast and Gynecology Med. Oncology,
Univ. Texas, MD Anderson Cancer Center, Houston, TX, USA. Journal of Clinical
Oncology (1998), 16(1), 348-353.
- Tamoxifen is currently the std. hormonal treatment of breast cancer, both for
metastatic disease and in the adjuvant setting.
- A new antiestrogen, toremifene, was approved recently for use in managing
metastatic breast cancer in postmenopausal women.
- Both agents have shown a significant hypocholesterolemic effect after
long-term administration. Tamoxifen has been assocd. with maintenance of bone
mineral d., a reduction in cardiac events, & a slightly increased risk of endometrial
cancer. Toremifene is not likely to be used as second-line therapy after tamoxifen
failure due to crossresistance.
2. Aromatase inhbitors
- A key step in estrogen biosynthesis include the conversion of androstenedione to
esterone catalyzed by aomatase enzyme.
- Blocking aromatase significantly lowers circulating estradiol.
- Anstrazole & letrozole are nonsteroidal aromatase inhibitors approved recently by
FDA as first-line treatment of postmenopausal women with hormone receptor
positive locally advanced or metastatic breast cancer.
- They competitively inhibit aromatase by binding to CYP450 subunit of the
enzyme.
- Both drug are used orally as 1-2.5 mg Tablets.
- Letrozole metabolized slowly in humans by CYP34A & found to be in vitro
inhibitor of CYP2C19, an isoform of CYP which is linked to aromatase enzyme.
- Anastrazole (Arimidex) & letrozole (Femara) are used for advanced breast cancer.
- They can cause hot flashes, nausea & vomiting.
3. GnRH Agonists & Antiandrogens
- Hormonal therapy of prostate cancer targets the removal of stimulatory effects
of male hormones (testosterone & dihydrotestosterone) on the prostate cancer
cells.
- Example of this is the use of agonists of gonadotropin-releasing hormone (GnRH),
also known as Luteinizing Hormone Releasing Hormone, LHRH.
CHEMO FINAL Page 41 of 46
- Although these agents initially increase testosterone level, they later decline its
level through down-regulation (desensitizing), which take up to 4 weeks & leads to
castrate testosterone level.
- Combination of GnRH agonists with antiandrogens will minimize the initial
testosterone level & prostate growth increase (flare phenomenon).
- The two most common GnRH agonists are leuprolide & goserelin.
- These are non-peptides differing from the natural hormone GnRH only at 2
locations.
- Leuprolide acetate (Lupron, Lupron Depot) is used as palliative therapy of
prostate carcinoma & endometrosis as iv injections (5 mg/ml).
- It can cause gynecomastia, impotence, hot flashes, nausea & vomiting.
- Goserelin (Zoladex) is indicated for advanced prostate carcinoma as iv injections
(3.6 mg/vial) or implants (10.8 mg). Toxicity: similar to lupron.
4. Antiandrogen Drugs
- Flutamide, bicalutamide & nilutamide are nonsteroidal antiandrogens which inhibit
androgen receptor translocation to the nucleus in target tissue, hypothalmus &
prostate, which block the action of testosterone & DHT.
- Flutamide & bicalutamide are used in combination with GnRH agonists to prevent
the flare phenomenon in treating prostate cancer.
- Flutamide (Eulexin) & bicalutamide (Casodex) are well absorbed orally.
- Flutamide is activated by metabolic oxidation to it’s a-hydroxy derivative,
an active metabolite.
- Flutamide & bicalutamide are indicated for metastaic prostate carcinoma, used as
capsule (125 mg) or tablets (50 mg), respectively.
- Toxicity: Gynecomastia, impotence, hot flashes, nausea & vomiting.
- Nilutamide (Nilandron) is another antiandrogen drug used as a single drug therapy
with surgical castration to block the action of testosterone & DHT.
CHEMO FINAL Page 42 of 46
- It is used as tablets (50 mg each) for metastatic prostate carcinoma.
- Toxicity: Hot flashes, nausea & vomiting.
5. GnRH Antagonists
- A new drug application was submitted for Abarelix which is a GnRH antagonist.
- It is a peptide with some structure similarity to the natural GnRH.
6. Combination Therapy
- Common & highly effective in cancer therapy.
- It depends on using drugs which individually are effective against a special cancer
type & using the individual agent at an effective dose.
- Each drug in the combination should have a unique mechanism of action & the
combination will be particularly useful if the drugs did not have overlapped
toxicities.
- The intent is to totally destroy cancer cells.
- Table: Text Book, pages 947-949.
- Metastasis requires the growth of a new network of
blood vessels. Angiogenesis is the recruitment of new blood vessels.
- Tumor angiogenesis is the proliferation of a network of blood vessels
that penetrates into cancerous growths, supplying nutrients, oxygen & removing
waste products.
- Angiogenesis is directly related to metastasis.
- Angiogenesis may be induced by increased production of angiogenic factors
or suppressed production of angiostatic factors
- The use of anti-angiogenic compounds in cancer area started to attract more
attention with the discovery of the first pro-angiogenic molecules bFGF & VEGF
7. ANGIOGENESIS & ONCOLOGY
- Angiogenesis inhibitors were found to restrain the growth of primary tumors and
reduce their metastasis rate by 20-folds.
- Several anti-angiogenic compounds currently undergoing evaluation in phase I- III
clinical trials either alone or combined with cytotoxic therapeutics.
- Certain tumor dormancy for several years is attributed to the lack of
angiogenesis.
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- Unlike standard cancer drugs, angiogenesis inhibitors target dividing endothelial
cells rather than tumor cells & other angiogenesis mediators.
- Anti-angiogenic drugs are not likely to cause bone marrow suppression,
gastrointestinal symptoms, or hair loss side effects.
- Anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in
check indefinitely, increasing the survival time &/or time of disease progression.
- Drug resistance is a major problem with conventional chemotherapy because most
cancer cells are genetically unstable & more susceptible to mutations &
hence, they likely tend to produce drug resistant cells.
- Angiogenic modulators target normal endothelial cells, which are genetically
stable, drug resistance may not develop.
- Anti-angiogenic therapy aims at stopping tumor growth which reduces the tumor
burden of the body & may increase the efficacy of other therapies.
- Limiting tumor number will enhance chemotherapy, hyperthermia, radiation, &
immune therapy & hence their com bination with anti-angiogenic therapy is
indicated.
Mechanisms of anti-angiogenic drugs
- The FDA approved Avastin (Bevacizumab) in February 2004.
- Avastin is approved for use in combination with intravenous 5-Fluorouracil-based
chemotherapy as a treatment for patients with first-line, or previously untreated,
metastatic cancer of the colon or rectum.
- The Avastin FDA approval is based on data from a large, placebo controlled,
randomized study demonstrating prolongation in survival of patients treated with
Avastin plus the IFL(5- FU/Leucovorin/CPT-11) chemotherapy regimen by
approximately 5 months, compared to patients treated with the IFL chemotherapy
regimen alone (20.3 months versus 15.6 months).
- AVASTIN™ (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody
that binds to & inhibits the biologic activity of human vascular endothelial growth
factor (VEGF) in in vitro & in vivo assay systems.
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- Bevacizumab has a molecular weight of approximately 149 kilodaltons.
- AVASTIN is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2
solution for intravenous (IV) infusion.
- AVASTIN is supplied in 100 mg & 400 mg preservative-free, single-use vials to
deliver 4 ml or 16 ml of AVASTIN (25 mg/ml).
- Toxicity: Gastrointestinal perforations/wound healing complications,
hemorrhage, hypertensive crises, nephrotic syndrome & congestive heart failure.
SUMMARY
5. Miscellaneous Agents/natural products:
- Epipodophyllotoxins: etoposide & teniposide
- Hydroxyurea, mitotane
- Retinoids: tretinoin, alitretinoin
- Camptothecins: topotecan & irinotecan
- Profimer
6. Hormonal Therapy:
- Antiestrogens: Tamoxifen & toremifene
- GnRH Agonists: Leuprolide acetate, Goserelin
- Antiandrogens: Flutamide, bicalutamide & nilutamide
- GnRH Antagonists: Abarelix
7. Antiangiogenic Drugs: Avastin
CHEMO FINAL Page 45 of 46
Angiogenesis inhibitors in clinical trials
Drug
BMS-275291
Dalteparin (Fragmin)
Suramin
2-Methoxyestrdiol
Thalidomide
CC-5013 (thalidomide
analog)
Combretastatin A4
phosphate
LY31761
Genistin (Soy isoflavone)
AE-941 (Neovastat)
Anti-VEGF antibody
(Avastin,
Bevacizumab)
Interferon-
PTK787/ZK 222587
VEGF-Trap
ZD6474
EMD 121974
Anti-Anb integrin
antibody
(Medi-522, Vitaxin)
Carboxyamidotriazole
Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Angiogenesis Mechanism
Blocks matrix breakdown
Blocks matrix breakdown
Blocks matrix breakdown
Inhibits endothelial cells
Inhibits endothelial cells
Inhibits endothelial cells
Origin
Synthetic
Natural origin
Synthetic
Natural product
Synthetic
Synthetic
Inhibits endothelial cells
Natural product
Inhibits endothelial cells/
Protein kinase C 
inhibitor
Inhibits endothelial cells
Block angiogenesis
activators
Block angiogenesis
activators
Synthetic
Block angiogenesis
activators
Block angiogenesis
activators
Block angiogenesis
activators
Block angiogenesis
activators
Inhibits endothelialspecific
integrin/survival signaling
Inhibits endothelialspecific
integrin/survival signaling
No specific mechanism
COX-2 inhibitor/no
specific
angiogenesis mechanism
COX-2 inhibitor/no
specific
Natural product
Natural product
Natural product
Natural product
Synthetic
Natural product
Synthetic
Natural origin
Natural product
Synthetic
Synthetic
Synthetic
CHEMO FINAL Page 46 of 46
Halofuginone HBr
(Tempostatin)
Interleukin-12
angiogenesis mechanism
No specific mechanism
Synthetic
No specific mechanism
Natural product