Download alkylating agent

Corso Integrato di Clinica Medica
ONCOLOGIA MEDICA
AA 2009 - 2010
CYTOTOXIC AGENTS
Prof. Alberto Riccardi
The history of chemotherapy. I.
The history of chemotherapy. II.
* no. of approved new
molecules for treatment
of cancer by Food and
Drug Administration
(FDA) per 5 - yr period:
relatively constant
through 1990, and
increased substantially
since then
CHEMOTHERAPEUTIC AGENTS
USED FOR CANCER TREATMENT
Chemotherapeutic agents used for cancer treatment
* commonly used cancer
chemotherapy agents grouped into 3
general categories:
- affecting DNA;
- affecting microtubules, and
- molecularly targeted agents;
* “usual doses” = tolerable and useful
(specific dose for a particular pt #
somewhat with particular treatment
protocol or plan of treatment);
- significant variation from these doses
be carefully verified to avoid or
anticipate toxicity
DIRECT DNA - INTERACTIVE
AGENTS
Direct DNA - interactive agents. I.
* DNA replication occurs during synthesis or S - phase of cell
cycle, with chr segregation of replicated DNA occurring in M
(mitosis) phase (G1 and G2 "gap phases”) precede S and M,
respectively;
- historically, chemotherapeutic agents divided into "phase nonspecific" (act in any phase of cell cycle) and "phase specific" (require cell at particular cell cycle phase to cause
greatest effect);
* once agent has acted, cells may progress to "checkpoints" in
cell cycle where drug - related damage (e.g., double - strand
breaks, DSBs) assessed, and either repaired or allowed to
initiate apoptosis;
- function of certain tumor - suppressor genes (e.g., p53) may
be to modulate checkpoint function
Direct DNA - interactive agents. II. Checkpoints
* p53 - Binding Protein 1 (53BP1)
- dependent checkpoint pathway
(G1 cell cycle arrest) triggered by
genotoxic events leading to
double - strand breaks (DSBs);
- epigenetic phosphorylation of
histone H2AX to γ - H2AX by
ATM (Ataxia Telangiectasia
Mutated) occurs at or near site of
DSBs and required for
subsequent phosphorylation of
53BP1 by ATM and localization of
53BP1 into nuclear foci;
- additionally, 53BP1 function critical for coupling ATM to many of its
downstream targets, including tumor suppressor p53 and Structural
Maintenance of Chromosomes protein 1 (SMC - 1);
* in case of Chk2 kinase (G2 chechpoint activation), coupling mechanism
to ATM independent of 53BP1
Direct DNA - interactive agents. III. p53
* with a G1 cell having low level of DNA damage, p53 protein hampers entering S
phase and copy its DNA (→
→ abnormal G1 cells undergo programmed cell death, i.e.,
apoptosis or growth arrest and DNA repair);
* with a G1 cell having high level of DNA damage and mutant p53 → cell divides and
undergoes clonal expansion, evolution and cancerization
ALKYLATING AGENTS
Alkylating agents. I. Formation of covalent DNA adducts
* alkylating agents (= class of cell cycle phase - nonspecific
agents) break down (either spontaneously or after normal organ
or tumor cell metabolism) to reactive intermediates that
covalently modify bases in DNA → cross - linkage of DNA
strands or appearance of breaks in DNA, as result of repair
efforts;
* “broken" or “cross - linked” DNA intrinsically unable to
complete normal replication or cell division (with being, in
addition, potent activator of cell cycle checkpoints and further
activates cell - signaling pathways precipitating apoptosis)
Alkylating agents. II.
* alkylating agents work by 3
# mechanisms, achieving
same end result = disruption of
DNA function and cell death:
- 1st mechanism: alkylating
agent (pink stars, above)
attaches alkyl groups (small
carbon compounds = pink
triangles, middle) to DNA
bases;
- alteration → DNA
fragmented by repair enzymes
in attempts to replace
alkylated bases (below);
- alkylated bases prevent
DNA synthesis and RNA
transcription from affected
DNA
Alkylating agents. III.
* 2nd mechanism =
formation of cross - bridges
(= bonds between atoms in
DNA);
- in process (middle), two
bases (pink linkages) linked
together by alkylating agent
having two DNA binding
sites;
- bridges formed within
single molecule of DNA
(below) or cross - bridge may
connect two different DNA
molecules;
- cross - linking prevents
DNA from being separated for
synthesis or transcription
Alkylating agents. IV.
* 3rd mechanism: induction
of mispairing of nucleotides
(purines = adenine, A, and
guanine, G, and pyrimidines =
thymine, T, and cytosine, C)
leading to mutations;
- in normal DNA double
helix, A always pairs with T
and G always pairs with C;
- below, alkylated G bases
may erroneously pair with T;
- with altered pairing not
corrected, it leads to
permanent mutation
Alkylating agents. V. Toxicity
* all alkylating agents share similar toxicities:
myelosuppression, alopecia, gonadal dysfunction, mucositis
and pulmonary fibrosis;
- may cause "second neoplasms", particuraly leukemia, many
yrs after use (especially in low doses for protracted periods);
- alkylating agents # greatly in spectrum of normal organ
toxicities
Alkylating agents. VI. Cyclophosphamide
* inactive unless metabolized by liver to 4 - hydroxy cyclophosphamide, which decomposes into alkylating species and to
chloroacetaldehyde and acrolein;
- acrolein causes chemical cystitis (= hydration be maintained while
using cyclophosphamide);
- severe cystitis effectively treated with mesna (2 - mercapto ethanesulfonate)
Alkylating agents. VII. Cyclophosphamide
* sporadic interstitial pneumonitis (→
→ pulmonary fibrosis);
- cardiac dysfunction may occur with high doses
cyclophosphamide (used in conditioning regimens for bone
marrow transplant);
* liver disease impairs drug activation
Alkylating agents. VIII. Ifosfamide
* ifosfamide = cyclophosphamide analogue more slowly
activated in liver;
- requires coadministration of mesna to prevent bladder injury;
- central nervous system (CNS) effects, including somnolence,
confusion and psychosis (related to low body surface area or
presence of nephrectomy)
ALKYLATING AGENTS. I.
Drug
Examples of usual
doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Alkylatorsa
Cyclophosphamide
400 - 2000 mg / m2 IV
100 mg / m2PO qd
Marrow
(relative platelet sparing)
Cystitis
Common alkylatora
Cardiac (high dose)
Liver
metabolism
required to activate to
phosphoramide
mustard + acrolein
Mesna protects
against "high - dose" bladder
damage
Ifosfamide
1.2 g / m2 / day qd x5 +
mesna
Myelosuppressive
Bladder
Neurologic
Metabolic acidosis
Neuropathy
Isomeric analogue of
cyclophosphamide
More lipid soluble
Greater activity vs testicular
neoplasms and sarcomas
Must use mesna
a Common alkylator: myelosuppression, alopecia,
pulmonary fibrosis, infertility and teratogenesis
Alkylating agents. IX. Mechlorethamine
* several alkylating agents less commonly used;
* nitrogen mustard (mechlorethamine) decomposes rapidly in
aqueous solution (to potentially yield a bifunctional carbonium
ion);
- be administered shortly after preparation into a rapidly
flowing intravenous line (with moderate nausea);
- aseptic thrombophlebitis frequent, even without infiltration;
- used topically as a dilute solution in cutaneous lymphomas,
with frequent hypersensitivity reactions
Alkylating agents. IXbis. Mechlorethamine
* powerful vesicant (infiltration symptomatically
ameliorated by infiltration of affected site with 1 / 6 M
thiosulfate)
Alkylating agents. X.
* chlorambucil → myelosuppression, azoospermia, nausea and
pulmonary side effects;
* busulfan → profound, late onset myelosuppression, alopecia
and pulmonary toxicity (relatively "lymphocyte sparing“), with
its routine use in treatment of CML curtailed by imatinib
(Gleevec) or dasatinib;
- still employed in transplant preparation regimens;
* melphalan: variable oral bioavailability and undergoing
extensive binding to albumin and alfa1 - acidic glycoprotein;
- prominent activity in multiple myeloma
ALKYLATING AGENTS. II.
Drug
Examples of
usual doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Alkylatorsa
Mechlorethamine
6mg / m2 IV day 1 and
day 8
Marrow
Vesicant
Nausea
Chlorambucil
1- 3 mg / m2 qd PO
Marrow
Common alkylatora
Melphalan
8 mg / m2 qd x 5, PO
Marrow (delayed nadir)
GI (high dose)
Topical use in cutaneous
lymphoma
Decreased renal function
delays clearance
a Common alkylator: myelosuppression, alopecia,
pulmonary fibrosis, infertility and teratogenesis
Alkylating agents. XI. Nitrosureas
* carmustine (BCNU) breaks down to carbamoylating species that
not only cause distinct pattern of DNA base pair - directed toxicity
but also covalently modify proteins;
- share relatively delayed bone marrow toxicity (possibly cumulative
and long - lasting);
- methyl CCNU (lomustine) → direct glomerular and tubular damage
(related to dose and time of exposure)
Alkylating agents. XIbis. Streptozotocin
* streptozotocin unique, in that its glucose - like structure conveys
specific toxicity to islet cells of pancreas (for whose derivative tumor
types prominently indicated) as well as causing renal toxicity as
Fanconi syndrome (= amino aciduria, glycosuria and renal tubular
acidosis)
ALKYLATING AGENTS. III.
Drug
Examples of usual
doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Alkylatorsa
200 mg / m2 IV
150 mg / m2 PO
Marrow
(delayed nadir)
GI, liver (high dose)
Renal
Marrow
Lomustine (CCNU) 100 - 300 mg / m2 PO
(delayed nadir)
Carmustine
(BCNU)
a Common alkylator: delayed myelosuppression, alopecia,
pulmonary fibrosis, infertility and teratogenesis
-
-
Alkylating agents. XII.
* procarbazine metabolized in liver and possibly in tumor cells to
yield a variety of free radical and alkylating species;
- beside myelosuppression, it causes hypnotic and other CNS
effects, including vivid nightmares;
- can cause disulfiram - like syndrome on ingestion of ethanol
(disulfiram = drug used for treatment of chronic alcoholism by
producing an acute sensitivity to alcohol = hangover, flushing of
skin, accelerated heart rate, shortness of breath, nausea, vomiting,
headache. visual disturbances, mental confusion, postural fainting ±
circulatory collapse);
* altretamine (formerly hexamethyl - melamine) and thiotepa give
rise to alkylating species (nature of DNA damage not well
characterized);
- thiotepa used for intrathecal treatment of neoplastic meningitis
Alkylating agents. XIII. Dacarbazine
* dacarbazine (DTIC) activated in liver to yield highly reactive
methyl diazonium cation;
- only modest myelosuppression 21 - 25 days after a dose but
prominent nausea on day 1;
- temozolomide structurally related to dacarbazine but
designed to be activated by nonenzymatic hydrolysis in tumors
and bioavailable orally
ALKYLATING AGENTS. IV.
Drug
Examples of usual
doses
Toxicity
Interactions,
Issues
Direct DNA - interacting agents
Alkylatorsa
Dacarbazine
375 mg / m2 IV day 1 and
day 15
Marrow
Nausea
Flulike
Metabolic activation
Procarbazine
100 mg / m2 / day qd x14
Marrow
Nausea
Neurologic
Common alkylatora
Liver and tissue
metabolism required
Disulfiran - like effect with
ethanol
Acts as MAOI
HBP after tyrosine - rich
foods
a Common
alkylator: modest myelosuppression,
alopecia, pulmonary fibrosis, infertility and teratogenesis
MAOI = monoamine oxidase inhibitors; HBP = high blood pressure
ALKYLATING AGENTS. V.
Drug
Examples of usual
doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Alkylators
Temozolomide
150 - 200 mg / q28d or
75 mg / m2qd x6 - 7 vks
Altretamine (formerly 260 mg / m2 / day qd x
14 - 21 as 4 divided oral
hexa - methyl doses
melamine)
Nausea / vomiting
Headache / fatigue
Constipation
Infrequent
myelosuppression
Nausea
Neurologic
(mood swing)
Neuropathy
Marrow (less)
Liver activation
Barbiturates enhance /
cimetidine diminishes
Alkylating agents. XIV. Cisplatin
* cisplatin discovered fortuitously by observing that bacteria in
electrolysis solutions could not divide;
- only cis diamine configuration active as antitumor agent
(hypothesized that in intracellular environment, chloride is lost
from each position, being replaced by a water molecule, with
resulting positively charged species being efficient bifunctional
interactor with DNA, forming “Pt - based cross - links”)
Alkylating agents. XV. Platin derivatives
Purine
synthesis
Pyrimidine
synthesis
Ribonucleotides
“adducts” formed
with DNA
Deoxyribonucleotides
transcription and replication
inhibited by formation of mainly
intrastrand crosslinks
DNA
RNA (transfer, messenger, ribosomal)
NH3
G
Pt
Proteins
Enzymes
Microtubules
NH3
G
Alkylating agents. XVI. Cisplatin
* cisplatin requires administration with adequate hydration,
including forced diuresis with mannitol to prevent kidney
damage (even with hydration, gradual ↓ in kidney function
common, along with noteworthy anemia);
- hypomagnesemia frequently occurs → hypocalcemia and
tetany;
- myelosuppression less common than with other alkylating
agents;
- chronic vascular toxicity (Raynaud's phenomenon, coronary
artery disease) as unusual toxicity
Alkylating agents. XVIbis. Cisplatin
* other common toxicities include
neurotoxocity (with stocking - and
- glove sensorimotor neuropathy)
and hearing loss (in 50% of pts
treated with conventional doses);
* intensely emetogenic, requiring
prophylactic antiemetics
Alkylating agents. XVII. Carboplatin and oxaliplatin
* with carboplatin, less nephro -, oto and neurotoxicity;
- myelosuppression more frequent;
- as drug exclusively cleared through
kidney, adjustment of dose for creatinine
clearance accomplished through use of
various dosing nomograms;
* oxaliplatin = platinum analog with
noteworthy activity in colon cancers
refractory to other treatments;
- prominently neurotoxic
ALKYLATING AGENTS. VI.
Drug
Examples of usual doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Alkylators
Cisplatin
20 mg / m2 qd x 5 IV 1 q 3 - 4 vks
or
100–200 mg / m2 / dose IV q3–4 vks
Nausea
Maintain high urine flow;
Neuropathy
osmotic diuresis, monitor
Auditory
intake / output K+, Mg2+
Marrow platelets > WBCs Emetogenic - prophylaxis
Renal Mg2+, Ca2+
needed
Full dose if CrCl > 60 mL /
min and tolerate fluid push
Carboplatin
365 mg / m2IV q 3 - 4 vks as
adjusted for CrCl
Marrow platelets > WBCs Reduce dose according to
Nausea
CrCl: to AUC of 5 – 7 mg /
Renal (high dose)
mL / min [AUC = dose /
(CrCl + 25)]
Oxaliplatin
130 mg / m2q 3wks over 2h
or
85 mg / m2 q 2vks
Nausea
Anemia
Acute reversible
neurotoxicity; chronic
sensory neurotox icity
cumulative with dose;
reversible
laryngopharyngeal spasm
CrCl, creatinine clearance; AUC, area under the curve
ANTITUMOR ANTIBIOTICS
Antitumor antibiotics
* antitumor antibiotics produced by bacteria that in nature
appear to provide chemical defense against hostile
microorganisms;
- bind to DNA directly and frequently undergo electron transfer
reactions to generate “free radicals” (= atoms, molecules or
ions, on open shell configuration, with unpaired electrons
causing them to be highly chemically reactive) in close
proximity to DNA → “oxidative stress” (caused by imbalance
between production of reactive oxygen and biological system's
ability to detoxify reactive intermediates or easily repair
resulting damage) → DNA damage in form of “single - strand
breaks” or “cross - links”
Antitumor antibiotics and free radicals
* = atoms, molecules or ions, on open shell configuration, with
unpaired electrons causing them to be highly chemically reactive
ANTITUMOR ANTIBIOTICS
TOPOISOMERASE POISONS
Antitumor antibiotics. I. Topoisomerase poisons. I.
* topoisomerase enzimes relax torsionally strained DNA
(supercoiled, important for DNA packaging within cell)
allowing DNA double helix to separate and replicate;
- subsequently religates cleaved strands;
- topoisomerase poisons = natural products or
semisynthetics derived from plants modifying enzymes
(topoisomerases) regulating capacity of DNA to “unwind”
and “religate” allowing normal replication or transcription
Antitumor antibiotics. II. Topoisomerases. II.
* topoisomerase I: creates “single - strand breaks” that
then rejoin following passage of other DNA strand through
break (in S - phase, topoisomerase I - induced, not
promptly resealed breaks lead to progress of replication
fork off end of DNA strand → DNA damage is potent signal
for induction of apoptosis);
- topoisomerase II: creates “double - strand breaks”
through which another segment of DNA duplex (double stranded DNA) passes before rejoining
Antitumor antibiotics. IIbis. Topoisomerase poisons. IIbis.
* topoisomerase I inhibitors (derivatives of camptothecin,
a Chinese tree) responsible for unwinding DNA strand by
introducing “single - strand breaks” and allowing rotation
of one strand about other = promote stabilization of DNA
linked to topoisomerase I in so - called “cleavable
complex”;
- etoposide: analogous action with topoisomerase II
Antitumor antibiotics. III. Topoisomerase I poisons. I.
Topo 1
inhibitor
Excessive torsion of
DNA
DNA
replication
Cutting step
Topo 1
action
Relaxation
Closing step
Closing step inhibition
Cell death
Antitumor antibiotics. IIIbis.
Topoisomerase poisons. Ibis
a
b
* a) normally, topoisomerase I introduces a nick in DNA backbone (so - called
“cleavable complex”) allowing rotation of one strand around other, thus
releasing torsional strain which otherwise accumulates in front of advancing
replication fork (large arrow);
- DNA break extremely transient and religated almost immediately at same
time that topoisomerase I releases other strand;
* b) poison drug (e.g., irinotecan, black oval with C) binds to topoisomerase I nicked DNA complex (so - called “cleavable complex”), preventing religation of
nicked strand and release of enzyme;
[- eventually, replication fork collides with complex, causing formation of
double - strand break]
Antitumor antibiotics. IV. Topoisomerase I poisons. III.
* owing role of topoisomerase I in procession of
replication fork, topoisomerase I poisons cause lethality if
topoisomerase I - induced lesions made in S - phase;
(- DNA damage in any cell cycle phase, but cells with p53
and Rb pathway lesions tend to arrest in S - phase or G2 of
cell cycle, as result of defective checkpoint mechanisms)
Antitumor antibiotics. V. Topoisomerase I poisons. IV.
Camptothecin derivatives
* two camptothecin derivatives approved and used in
cancer chemotherapy:
* topotecan, in gynecologic tumors and small cell lung
cancer;
- toxicity limited to myelosuppression and mucositis;
* irinotecan (CPT - 11), in colon carcinoma;
- in addition to myelosuppression, it causes secretory
diarrhea (related to toxicity of metabolite SN - 38)
effectively treated with loperamide or octreotide
Antitumor antibiotics. VI. Topoisomerase II poisons. I.
Etoposide. I.
* synthetically derived from plant product
podophyllotoxin, it binds directly to topoisomerase II and
DNA in reversible ternary complex;
- stabilizes covalent intermediate in enzyme's action
where enzyme is covalently linked to DNA (historically, this
"alkali - labile" DNA bond = first hint that enzyme
topoisomerase exists);
- prominent G2 arrest, reflecting action of DNA damage
checkpoint
Antitumor antibiotics. VII.
Mechanism of Topoisomerase II
action. II.
* Step 1: Topo II binds non covalently to gate (G) duplex (double
- stranded DNA) (so called because
it opens like a gate);
- Step 2: G duplex - topo II complex
binds at crossover region with
transported (T) duplex (so called
because this duplex passes through
G duplex);
- Step 3: ATP binds and promotes formation of tridimensional
topological complex;
- Step 4: Mg2+ - dependent cleavage of G duplex;
- Step 5: T duplex passes through gap formed in G duplex;
- Step 6: G duplex is re - ligated and bound ATP hydrolysed;
- enzyme now free to enter another catalytic cycle
Antitumor antibiotics. VIII. Topoisomerase II poisons. III.
Etoposide. III.
* prominent clinical effects include myelosuppression,
nausea and transient hypotension (related to speed of
administration);
- mild vesicant, but relatively free from other large - organ
toxicities;
* with at high doses or very frequently, topoisomerase II
inhibitors may cause mixed lineage secondary acute
leukemia (MLL) associated with chr 11q23 abnormalities in
up to 1% of exposed pts
ANTITUMOR ANTIBIOTICS. I. TOPOISOMERASES POISONS
Drug
Examples of usual
Toxicity
doses
Direct DNA – interacting agents
Interactions,
issues
Antitumor antibiotics
Topotecan
Irinotecan (CPT
11)
Etoposide
(VP16 - 213)
20 mg / m2IV q3–4vks over
30 min
or 1.5–3 mg / m2q3–4vks
over 24 h
or 0.5 mg / m2 / day over 21
days
Marrow
Mucositis
Nausea
Mild alopecia
Reduce dose with renal
failure
No liver toxicity
100 - 150 mg / m2IV over 90 Diarrhea: "early onset" with Prodrug requires enzymatic
min q3 - 4vks
cramping, flushing,
clearance to active drug"SN
2
or 30 mg / m / day over
vomiting; "late onset" after
38"
120 h
several doses
Early diarrhea likely due
Marrow
tobiliary excretion
Alopecia
Late diarrhea, use "high Nausea
dose" loperamide(2 mg q2 Vomiting
4h)
Pulmonary
100–150 mg / m2IV qdx3–5d
Or 50 mg / m2 PO qdx 21d
or up to 1500 mg / m2 /
dose (high dose with stem
cell support)
Marrow (WBCs > platelet)
Alopecia
Hypotension
Hypersensitivity(rapid IV)
Nausea
Mucositis (high dose)
Hepatic metabolism—renal
30%
Reduce doses with renal
failure
Schedule - dependant (5
day better than 1 day)
Late leukemogenic
Accentuate antimetabolite
action
ANTITUMOR ANTIBIOTICS
ANTHRACYCLINES
Antitumor antibiotics. IX. Anthracyclines. I.
* doxorubicin (Adriamycin®) intercalates into
DNA, with altering DNA structure, replication
and topoisomerase II function;
- also, undergoes reduction reactions by
accepting electrons into its quinone ring
system, with capacity to undergo
“reoxidation” and to form dangerous “reactive
oxygen radicals” (ROS = reactive molecules
containing oxygen atom, either as oxygen
ions and peroxides) after reoxidation;
* myelosuppression, alopecia, nausea, and
mucositis;
- acute cardiotoxicity in form of atrial and
ventricular dysrhythmias (rarely of clinical
significance)
Antitumor antibiotics. X. Anthracyclines. II.
* #, cumulative doses > 550 mg / m2 associated with 10%
incidence of chronic cardiomyopathy [(incidence of
cardiomyopathy related to schedule = peak serum
concentration, with low dose (frequent treatment or
continuous infusions) better tolerated than intermittent
higher dose exposures)]
Antitumor antibiotics. Xbis. Anthracyclines. IIbis.
Pathway of anthracycline - induced
chronic cardiac dysfunction
* chronic cardiotoxicity related to iron - catalyzed
oxidation (oxidative stress damage; ODFR, oxygen derived free radicals = ROS) ) and reduction of doxorubicin
(not to topoisomerase action)
Antitumor antibiotics. Xter. Anthracyclines. IIter.
* doxorubicin's cardiotoxicity ↑ when given together with
trastuzumab (Herceptin, anti - HER - 2 / neu Ab);
- radiation recall or interaction with concomitantly
administered radiation frequently cause local site
complications
Antitumor antibiotics. XI. Anthracyclines. III.
* powerful vesicant, with necrosis
of tissue at 4 - 7 days after
extravasation;
- be administered into rapidly
flowing intravenous line, with
dexrazoxane (Cardioxane©) being
antidote to doxorubicin - induced
cardiotoxicity and extravasation (it
chelates iron, but precise
protection mechanism not known); doxorubicin extravasation
- doxorubicin metabolized by liver
(doses ↓ by 50 - 75% with liver
dysfunction)
Antitumor antibiotics. XII. Anthracyclines. IV.
* daunorubicin© closely related to
doxorubicin and actually introduced first
into leukemia treatment (preferable to
doxorubicin owing to less mucositis and
colonic damage);
* idarubicin© also used in acute myeloid
leukemia and preferable to daunorubicin in
activity
Antitumor antibiotics. XIII. Anthracyclines. V.
* encapsulation of
daunorubicin into liposomal
formulation attenuates
cardiac toxicity and antitumor
activity (e.g., in Kaposi's
sarcoma and ovarian cancer)
* liposome = tiny bubble (vesicle), made out of same material as cell
membrane, can be filled with drugs and used to deliver drugs for cancer
and other diseases;
- membranes usually made of phospholipids (= molecules having a head
and a tail group), with head attracted to water and tail (made of long
hydrocarbon chain) repelled by water
Antitumor antibiotics. XIV. Mitoxantrone. I.
* mitoxantrone (mainly
topoisomerase II inhibitor, also
disrupting DNA repair) = synthetic
compound designed to
recapitulate features of
doxorubicin but with less
cardiotoxicity (comparing ratio of
cardiotoxic to therapeutic effective
doses);
- still associated with 10%
incidence of cardiotoxicity at
cumulative doses of > 150 mg /
m2;
- alopecia
Antitumor antibiotics. XV. Mitoxantrone. II
* cases of acute promyelocytic leukemia (APL) shortly
after exposure of pts to mitoxantrone (especially in
adjuvant treatment of breast cancer);
- while chemotherapy - associated leukemia generally of
acute myeloid type, APL (acute promyelocytic leukemia)
arising after mitoxantrone has typical 15;17 chr
translocation (with breakpoints of translocation at
topoisomerase II sites, preferred sites of mitoxantrone
action, clearly linking action of drug to leukemia)
ANTITUMOR ANTIBIOTICS. II. ANTHRACYCLINES
Drug
Examples of usual
doses
Toxicity
Interactions,
issues
Direct DNA - interacting agents
Antitumor antibiotics
Doxorubicin and
daunorubicin
45 – 60 mg / m2 dose q 3–4
vks
or 10– 30 mg / m2dose
q week
or continuous - infusion
regimen
Marrow
Mucositis
Alopecia
Cardiovascular acute /
chronic
Vesicant
Heparin aggregate;
coadministration increases
clearance
Acetaminophen, BCNU
increases liver toxicity
Radiation recall
Idarubicin
10 – 15 mg / m2 IV q3vks
or 10 mg / m2 IV qdx3
Marrow
Cardiac (less than
doxorubicin)
None established
Epirubicin
150 mg / m2 IV q3vks
Marrow
Cardiac
None established
Mitoxantrone
12 mg / m2 qd x3
or 12–14 mg / m2 q3 wks
Marrow
Cardiac (less than
doxorubicin)
Vesicant (mild)
Blue urine, sclerae, nails
Interacts with heparin
Less alopecia, nausea
than doxorubicin
Radiation recall
Antitumor antibiotics. XVI. Bleomycin. I.
* bleomycin = mixture of glycopeptides (mainly from bacterium
Streptomyces verticillus) with unique feature of forming complexes
with Fe2+ while also bound to DNA;
- oxidation of Fe2+ gives rise to superoxide and hydroxyl radicals;
- cleared rapidly, but augmented skin and pulmonary toxicity in
presence of renal failure → doses reduced by 50 - 75% when
creatinine clearance < 25 mL / min;
- not vesicant (administered intravenously, intramuscularly or
subcutaneously)
Antitumor antibiotics. XVII. Bleomycin. II.
* little, if any, myelosuppression;
- common side effects include fever and chills, facial
flush, Raynaud's phenomenon and hyperpigmentation of
skin;
- hypertension can follow rapid iv administration;
- incidence of anaphylaxis with early preparations of drug
→ administering test dose of 0.5 - 1 unit before rest of dose
Antitumor antibiotics. XVIII. Bleomycin. II.
* bleomycin inactivated by
bleomycin hydrolase, whose
concentration ↓ in skin
(hyperpigmentation) and lung
(pulmonary fibrosis)
Antitumor antibiotics. XIX. Bleomycin. IV.
* pulmonary fibrosis = most feared
complication of bleomycin treatment
(↑
↑ incidence at > 300 cumulative
units administered and minimally
responsive to treatment, e.g., with
glucocorticoids);
- earliest indicator of adverse effect
= ↓ in DLCO (Diffusing capacity of
Lung for Carbon monoxide), but
cessation of drug immediately its
documentation not prevents further
decline in pulmonary function
Antitumor antibiotics. XX. Bleomycin. V.
* because bleomycin - dependent electron transport
dependent on O2, bleomycin toxicity may become apparent
after exposure to transient very high PIO2 (= Partial
pressure of Inspired Oxygen);
- during surgical procedures, pts with prior exposure to
bleomycin be maintained on lowest PIO2 consistent with
maintaining adequate tissue oxygenation
Antitumor antibiotics. XXI. Mytomicin C
* mitomycin C (undergoing reduction of its quinone function)
generates a bifunctional DNA alkylating agent;
- broadly active antineoplastic agent with a no. of
unpredictable toxicities, including delayed bronchospasm (12 14 h after dosing) and chronic pulmonary fibrosis (more
frequent at doses of 50 - 60 mg / m2);
- cardiomyopathy may occur, especially after prior radiation
therapy;
- notable vesicant and causes substantial nausea and
vomiting;
* used for intravesical instillation for curative treatment of
superficial transitional bladder carcinomas and, with radiation
therapy, for curative treatment of anal carcinoma
Antitumor antibiotics. XXIbis. Mytomicin C
* hemolytic / uremic syndrome (hemolytic anemia,
thrombocytopenia and acute renal failure) with ultimate mortality rate
of 25 - 50% (poorly treated by conventional component support and
exchange transfusion)
ANTITUMOR ANTIBIOTICS. III. VARIOUS
Drug
Examples of usual
Toxicity
doses
Direct DNA - interacting agents
Interactions,
issues
Antitumor antibiotics
Bleomycin
15–25 mg / dq dx 5 IV bolus or
continuous IV
Pulmonary
Skin effects
Raynaud's
Hypersensitivity
Inactivate by bleomycin
hydrolase (decreased in lung /
skin)
O2 enhances pulmonary toxicity
Cisplatin - induced decrease in
CrCl may increase skin / lung
toxicity
Reduce dose if CrCl < 60 mL /
min
Actinomycin D
10–15 g / kg / day qdx5 IV
bolus
Marrow
Nausea
Mucositis
Vesicant
Alopecia
Radiation recall
Mitomycin C
6–10 mg / m2q6 vks
Marrow
Vesicant
Hemolytic - uremic
syndrome
Lung
CV - heart failure
Treat superficial bladder cancers
by intravesical infusion
Delayed marrow toxicity
Cumulative marrow toxicity
CrCl, creatinine clearance; CV, cardiovascular
ANTIMETABOLITES
Antimetabolites. I.
* “broad” definition of antimetabolites = compounds with
structural similarity to precursors of purines or
pyrimidines, or compounds interfering with purine or
pyrimidine synthesis;
- cause DNA damage indirectly, through misincorporation
into DNA, abnormal timing or progression through DNA
synthesis or altered function of pyrimidine and purine
biosynthetic enzymes;
- greatest toxicity to cells in S - phase and degree of
toxicity ↑ with duration of exposure;
- common toxic effects include stomatitis, diarrhea and
myelosuppression (second malignancies not associated)
METHOTREXATE
Antimetabolites. II. Methotrexate. I.
* both reduced folates [substrates =
coemzymes in a no. of single - carbon transfer reactions, e.g., involved in synthesis
of dTMP (2 - deoxythymidine - 5 - phosphate)
from dUMP (2’ - deoxyuridine - 5 phosphate)] and methotrexate (antifolate
drug) transported into cells by folate carrier;
- methotrexate ↓ dihydrofolate reductase,
which regenerates reduced folates from
oxidized folates (produced when thymidine
monophosphate, dTMP, formed from
deoxyuridine monophosphate, dUMP);
- without reduced folates, cells die
("thymine - less" death)
Antimetabolites. III.
Methotrexate. II.
* methotrexate (MTX) enters cell
through reduced folate carrier (a)
using an endocytic pathway
activated by folate receptor (b);
- after entering cell,
methotrexate is polyglutamated
(Glu) by enzyme folyl polyglutamate synthase (C);
- methotrexate and its polyglutamates ↓ enzyme dihydro - folate reductase
(d), blocking conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4,
coenzyme in many reactions, especially in metabolism of nucleic acids);
- as tetrahydrofolate stores depleted, ↓ thymidylate (TMP) synthesis (e)
and, ultimately, ↓ DNA synthesis (f);
- long - chain polyglutamates of MTX = same affinity as MTX for target
enzyme dihydrofolate reductase, but markedly ↑ inhibitory effects on both
thymidylate synthesis (e) and purine biosynthesis (f), required for RNA
production]
Antimetabolites. IV. Methotrexate. III.
* leucovorin = folinic acid (5 - formyl derivative of tetrahydrofolic
acid = N5 - formyltetrahydrofolate) readily converted to other reduced
folic acid derivatives, e.g. N5 - tetrahydrofolate (= without requiring
dihydrofolate reductase conversion);
→ functioning as vitamin unaffected by inhibition of dihydrofolate
reductase by drugs (e.g., MTX) → vitamin activity equivalent to folic
acid;
- this bypasses inhibition of dihydrofolate reductase and rescue
cells from methotrexate damage, which is maintained in cells by
polyglutamylation;
* → therefore, folinic acid allows that some purine / pyrimidine
synthesis occurs in presence of dihydro - folate reductase inhibition
by methotrexate → some normal DNA replication and RNA
transcription processes can proceed
Antimetabolites. V. Methotrexate. IV.
* from these properties, design of "high - dose"
methotrexate regimens with leucovorin rescue of normal
marrow and mucosa as part of curative approaches to
osteosarcoma in adjuvant setting and hematopoietic
neoplasms of children and adults
Antimetabolites. VI. Methotrexate. V.
* methotrexate cleared by kidney via both glomerular
filtration and tubular secretion (toxicity ↑ by renal
dysfunction and drugs undergoing tubular secretion,
e.g., salicylates, probenecid and nonsteroidal anti inflammatory agents);
- with normal renal function, 15 mg / m2 leucovorin will
rescue 10–8 to 10–6 M methotrexate in 3 - 4 doses (with ↓
creatinine clearance, leucovorin doses of 50 - 100 mg /
m2 continued until methotrexate levels < 5 x 10–8 M)
Antimetabolites. VII. Methotrexate. VI.
* in addition to bone marrow suppression and mucosal irritation,
methotrexate can cause renal failure itself at high doses owing to
crystallization in renal tubules (→
→ high - dose regimens require
alkalinization of urine with ↑ flow by hydration);
* methotrexate sequestered in third - space collections (e.g., pleural
effusions or ascitic fluids) and leech back into general circulation (→
→
prolonged myelosuppression);
- less frequent adverse effects include reversible ↑ in transaminases
and hypersensitivity - like pulmonary syndrome;
* chronic low - dose can cause hepatic fibrosis;
* when administered to intrathecal space, methotrexate can cause
chemical arachnoiditis and CNS dysfunction
Antimetabolites. VIII. Pemetrexed
* pemetrexed = novel, "multitargeted" folate - directed
antimetabolite = ↓ activity of several enzymes, including
dihydrofolate reductase, thymidylate synthetase and
glycinamide ribonucleotide formyltransferase → affects
synthesis of both purine and pyrimidine nucleic acid
precursors of both RNA and DNA;
- to avoid significant toxicity to normal tissues, pts receive
low - dose folate and vitamin B12 supplementation;
* activity against certain lung cancers and, in combination
with cisplatin, also against mesotheliomas
5 - FLUORURACIL
uracil
5 - fluouracil
Antimetabolites. IX. 5 - fluorouracil. I.
* 5 - fluorouracil (5 - FU) = early example of "rational" drug,
from observation that tumor cells incorporate radiolabeled
uracil more efficiently into DNA than normal cells, especially in
gut;
- 5 - FU metabolized in cells to 5 - fluorouridine - 5‘ monophosphate (FUMP), which (via # enzymatic reactions)
inhibits RNA and DNA synthesis, either by incorrectly
incorporating “false” bases into RNA and / or DNA or inhibiting
DNA thymidylate synthetase (TS);
* in addition, misincorporation leads to single - strand breaks
and RNA can aberrantly incorporate FUMP (5 - fluorouridine - 5‘
- monophosphate) and / or its derivatives;
* 5 - FU metabolized by dihydro - pyrimidine dehydrogenase
(DPD) → deficiency of enzyme → excessive toxicity from 5 - FU
Antimetabolites. X. 5 - fluorouracil. II.
* actually, 5 - FU converted into 3 main active metabolites:
- fluorodeoxyuridine monophosphate [FUMP → fluorouridine
diphosphate (FUDP) → active metabolite fluorouridine
triphosphate (FUTP) → RNA damage via FUTP interfering with
RNA synthesis];
- fluorodeoxyuridine monophosphate [FUMP →
fluorodeoxyuridine triphosphate (FUDP) → fluorodeoxyuridine
diphosphate (FdUDP) → fluorodeoxyuridine monophosphate
(FdUMP) → DNA damage via inhibition of thymidylate
synthetase], and
- fluorodeoxyuridine monophosphate [FUMP → fluorouridine
diphosphate (FUDP) → fluorodeoxyuridine diphosphate
(FdUDP) → fluorodeoxyuridine triphosphate (FdTDP) → DNA
damage via FdUTP interfering with DNA synthesis)
Antimetabolites. XI. 5 - fluorouracil. III.
* main mechanism of 5 - FU activation =
conversion to fluorouridine monophosphate
(FUMP, inhibiting thymidilate synthase)
(black), either directly by orotate
phosphoribosyl - transferase (OPRT, with
phosphoribosyl pyrophosphate, PRPP, as
cofactor) or indirectly via fluorouridine (FUR)
through actions of uridine phosphorylase
(UP) and uridine kinase (UK);
- FUMP then phosphorylated to fluorouridine
diphosphate (FUDP) (red), further
phosphorylated to RNA - active metabolite
fluorouridine triphosphate (FUTP) (black) or
converted to fluorodeoxyuridine diphosphate
(FdUDP) (red) by ribonucleotide reductase
(RR);
- in turn, FdUDP either be phosphorylated or dephosphorylated to
generate active metabolites FdUTP (interfering with DNA synthesis) and
FdUMP (still interfering with thymidilate synthase), respectively
Antimetabolites. XII. 5 - fluorouracil. IV.
* an alternative activation pathway
involves thymidine phosphorylase (TP),
catalyzin conversion of 5 - FU to
fluorodeoxyuridine (FUDR) →
phosphorylated by thymidine kinase
(TK) to FdUMP;
* dihydro - pyrimidine dehydrogenase
(DPD) - mediated conversion of 5 - FU
to dihydrofluorouracil (DHFU) = rate limiting step of 5 - FU catabolism in
normal and tumor cells (up to 80% of
administered 5 - FU broken down by
DPD in liver)
Antimetabolites. XIII. 5 - fluorouracil. V. Inhibition of DNA synthesis
via inhibition of thymidilate synthetase
* normally (red), in presence of
cofactor 5, 10 - methylene
tetrahydrofolate (as methyl donor),
thymidilate syntetase (TS) and 2’ deoxy - uridine - 5’ - mono - phosphate
(dUMP) form ternary complex,
enabling transfer of methyl group on ‘5
of dUMP to form thymidine - 5’ monophosphate (dUMP → dTMP);
- following 5 - FU and 5 - FdUMP
formation (black), methyl transfer does
not occurs (F atom in C5 of 5 - FdUMP
> tightly bound than H) → enzyme
trapped in slowly reversible ternary
complex;
= blocked formation of dTMP and availability of thymidine - 5’ triphosphate (dTTP) for DNA replication and repair ("genotoxic stress"
resulting from TS inhibition activates programmed cell death pathways)
Antimetabolites. XIV. 5 - fluorouracil. VI.
Inhibition of RNA synthesis
* 5 - FUTP: due to comparable size F
atom replacing H on ‘5 of uracil, 5 - FUTP
fluoronucleotide mimics UTP, is
recognized by RNA polymerases and 5 FU is incorporated in all classes of RNA
(full cytotoxicity stems from a
combination of numerous modifications
of RNA, rather than alteration of single
function)
Antimetabolites. XII. 5 - fluorouracil. V.
Antimetabolites. XVI. 5 - fluorouracil. VIII.
* iv administration of 5 - FU → bone marrow suppression
after short infusions and stomatitis after prolonged
infusions;
- less frequent toxicities include CNS dysfunction
(prominent cerebellar signs) and endothelial toxicity
(thrombosis, including pulmonary embolus and myocardial
infarction);
* leucovorin (folinic acid) ↑ activity of 5 - FU by promoting
formation of ternary covalent complex of 5 - FU, reduced
folate and TS
Antimetabolites. XVII. 5 - fluorouracil.
IX. Calcium folinate (leucovorin)
* administration of IV 5 FU and folinic acid
(leucovorin) ↑ efficacy (by
↑ binding of 5 - FU to its
target enzyme,
thymidylate synthase),
with ↑ in cancer
responses
Antimetabolites. XVII. 5 - fluorouracil.
IX. Calcium folinate (leucovorin)
* administration of
IV 5 - FU and folinic
acid (leucovorin) ↑
efficacy (by ↑
binding of 5 - FU to
its target enzyme,
thymidylate
synthase), with 3 fold ↑ in partial
responses
ORAL FLUOROPYRIMIDINES
Antimetabolites. XVIII. Capecitabine. I.
* oral bioavailability of 5 - FU varies unreliably, but
developed, orally administered analogues of 5 - FU (e.g.,
capecitabine) allow at least equivalent activity to many
parenteral 5 - FU - based approaches to refractory cancers
Antimetabolites. XIX. Capecitabine. II.
intestine
capecitabine
liver
capecitabine
tumor
CE
- not metabolized by
thymidine phosphorylase in
intestine, with ↓ GI toxicity;
- activated to 5 - FU
preferentially in tumors;
5‘ - DFCR
CyD
5‘ - DFUR
5‘ - DFCR
CyD
5‘ - DFUR
thymidine
phosphorylase
5 - FU
* after passing intestine as intact molecule, converted: 1) to 5´
´- deoxy - 5fluorocytidine (5’ - DFCR) by carboxylesterase (CE, almost exclusively in liver); 2)
to 5´
´- deoxy - 5 - fluorouridine (5’ - DFUR) by cytidine deaminase (CyD, high
concentrations in liver and various solid tumors), and 3) to 5 - FU in tumors by
thymidine phosphorylase (TP, > in tumors than in normal tissues)
ANTIMETABOLITES. I.
Drug
Examples of
Toxicity
Interactions,
usual doses
issues
Indirect DNA - interacting agents
Antimetabolites
Methotrexate
15 – 30 mg PO or IM
qd x 3 – 5
or 30 mg IV days 1
and 8
or 1.5 – 12 g / m2 /
day (with leucovorin)
Marrow
Liver / lung
Renal tubular
Mucositis
Rescue with
leucovorin
Excreted in urine
Decrease dose in
renal failure
NSAIDs increase renal
toxicity
Pemetrexed
200 mg / m2 q3 vks
Anemia
Neutropenia
Thrombocytopenia
5 - Fluorouracil
375 mg / m2IV qd x5
or 600 mg / m2IV days
1 and 8
Marrow
Mucositis
Neurologic
Skin changes
Supplement folate /
B12
Caution in renal
Toxicityfailure
enhanced by
Capecitabine
leucovorin
Dihydropyrimidine
dehydrogenase
deficiency increases
toxicity
Metabolized in tissues
665 mg / m2 bid
Diarrhea
Prodrug of 5 - FU due
continuous;
Hand - foot syndrome
to intratumoral
2
1250 mg / m bid 2 vks
metabolism
on / 1 off; 829 mg / m2
bid 2 vks on / 1 off +
60 mg / leucovorin
Antimetabolites. XX. Cytosine arabinoside
* cytosine arabinoside (Ara - C) incorporated into DNA (after
formation of ara - CTP = arabino - furanosylcytosine triphosphate) →
S - phase - related toxicity (especially used in hematologic
malignancies);
- maximal efficiency from continuous infusion schedules, with
uptake maximal at 5 - 7 micro M;
- can be administered intrathecally;
* adverse effects include nausea, diarrhea, stomatitis, chemical
conjunctivitis and cerebellar ataxia
cytarbine arabinose
sugar replacing ribose
in cytidine (left)
Antimetabolites. XXI. Gemcitabine
* gemcitabine = cytosine derivative
similar to Ara - C , incorporated into
DNA after anabolism to
triphosphate, rendering DNA
susceptible to breakage and repair
synthesis;
- # from Ara - C, gemcitabine induced lesions very inefficiently
removed;
- # from Ara - C, useful activity in
solid tumors, with limited non myelosuppressive toxicities
Antimetabolites. XXII.
6 - thioguanine and 6 - mercaptopurine
* 6 - thioguanine and 6 - mercaptopurine (6 - MP) for acute
myeloid leukemia;
- administered orally with variable bioavailability (6 - MP
metabolized by xanthine oxidase, requiring dose reduction when
used with allopurinol)
ANTIMETABOLITES. II.
Drug
Examples of
Toxicity
usual doses
Indirect DNA - interacting Agents
Interactions,
Issues
Antimetabolites
Cytosine
arabinoside
100 mg / m2 / day qd x 7
Marrow
Enhances activity of
by continuous infusion
Mucositis
alkylating agents
2
or 1 – 3 g / m dose IV
Neurologic (high dose) Metabolized in tissues by
bolus
Conjunctivitis (high dose)
deamination
Non cardiogenic
pulmonary edema
Gemcitabine
1000 mg / m2 IV weekly x7
Marrow
Nausea
Hepatic
Fever / "flu syndrome"
6 - mercaptopurine
75 mg / m2 PO
or up 500 mg / m2 PO
(high dose)
Marrow
Liver
Nausea
Variable bioavailability
Metabolized by xanthine
oxidase
Decrease dose with
allopurinol
Increased toxicity with
thiopurine
methyltransferase
deficiency
6 - thioguanine
2–3 mg / kg / day for up
to 3–4vks
Marrow
Liver
Nausea
Variable bioavailability
Increased toxicity with
thiopurine
methyltransferase
deficiency
Antimetabolites. XXIII.
Fludarabine phosphate and 2 - chlorodeoxyadenosine
* fludarabine phosphate = prodrug of F - adenine arabinoside (F ara - A) designed to ↓ susceptibility of ara - A to adenosine
deaminase;
- F - ara - A incorporated into DNA, with delayed cytotoxicity even in
cells with low growth fraction (e.g., chronic lymphocytic leukemia
and follicular B cell lymphoma);
- CNS and peripheral nerve dysfunction and myelosuppression (with
T cell depletion and possible opportunistic infections);
* 2 - chlorodeoxyadenosine = similar compound (activity in hairy cell
leukemia)
Antimetabolites. XXIV.
2 - deoxycoformycin and hydroxyurea
* 2 - deoxycoformycin inhibits adenosine
deaminase, with resulting ↑ in dATP levels →
inhibition of ribonucleotide reductase as well as
↑ susceptibility to apoptosis, particularly in T
cells;
- renal failure and CNS dysfunction notable
toxicities, in addition to immunosuppression;
* hydroxyurea inhibits ribonucleotide
reductase, resulting in S - phase block;
- orally bioavailable and useful for acute
management of myeloproliferative states
ANTIMETABOLITES. III.
Drug
Examples of
Toxicity
Interactions,
usual doses
issues
Indirect DNA - interacting agents
Antimetabolites
Fludarabine
phosphate
25 mg / m2IV qd x5
Marrow
Neurologic
Lung
Dose reduction with
renal failure
Metabolized to F– ara
converted to F– ara
ATP in cells by
deoxycytidine kinase
2 - chloro - deoxy
- adenosine
0.09 mg / kg / day
qd x7 as continuous
infusion
Marrow
Renal
Fever
Notable use in hairy
cell leukemia
Deoxycoformycin
4mg / m2IV every
other wk
Nausea
Immunosuppression
Neurologic
Renal
Excreted in urine
Reduce dose for renal
failure
Inhibits adenosine
deaminase
Hydroxyurea
20–50 mg / kg (lean
body weight) PO qd
or 1–3 g / d
Marrow
Nausea
Mucositis
Skin changes
Rare renal, liver, lung,
CNS
Decrease dose with
renal failure
Augments
antimetabolite effect
ANTIMETABOLITES. IV.
Drug
Examples of
Toxicity
Interactions,
usual doses
issues
Indirect DNA - interacting agents
Antimetabolites
Azacytidine
750 mg / m2 / week
or 150–200 mg / m2 /
dayx 5–10 (bolus) or
(continuous IV)
Marrow
Nausea
Liver
Neurologic
Myalgia
Use limited to
leukemia
Altered methylation of
DNA alters gene
expression
Azathioprine
1 - 5 mg / kg / day
Marrow
Nausea
Liver
Metabolized to 6MP,
therefore reduce dose
with allopurinol
Increased toxicity with
thiopurine
methyltransferase
deficiency
Antimetabolites. XXV. Asparaginese. I.
* asparaginase = bacterial enzyme causing breakdown of
extracellular asparagine required for protein synthesis in certain
leukemic cells → effectively stops tumor cell DNA synthesis, as it
requires concurrent protein synthesis → outcome of asparaginase
action therefore very similar to result of small - molecule
antimetabolites
Antimetabolites. XXVI. Asparaginese. II.
* being foreign protein, hypersensitivity reactions common, as
effects on organs such as pancreas and liver that normally
→ ↓ insulin secretion with
require continuing protein synthesis (→
hyperglycemia, ± hyperamylasemia and clotting function
abnormalities → close monitoring of clotting functions
accompany use of asparaginase);
- paradoxically, owing to depletion of rapidly turning over
anticoagulant factors, thromboses particularly affecting CNS also
seen with asparaginase
ANTIMETABOLITES. V.
Drug
Examples of
Toxicity
usual doses
Indirect DNA - interacting agents
Interactions,
issues
Antimetabolites
Asparaginase
25,000 IU / m2 q3–4 vks
or 6000 IU / m2 / day qod
for 3 - 4vks
or 1000–2000 IU / m2
for 10–20 days
Protein
synthesis
Clotting factors
Glucose
Albumin
Hypersensitivity
CNS
Pancreatitis
Hepatic
Blocks methotrexate
action
MITOTIC SPINDLE INHIBITORS
MITOTIC SPINDLE INHIBITORS. I.
* microtubules = cellular structures forming mitotic spindle,
composed of repeating noncovalent multimers of α - and β dimers of protein tubulin;
- in interphase cells, responsible for cellular "scaffolding"
along which various motile and secretory processes occur
(“cytoskeleton”)
MITOTIC SPINDLE INHIBITORS
VINCA ALCALOIDS
a | podophyllum peltatum (mayapple), producing podophyllotoxin, and b |
catharanthus roseus (Vinca rosea or rosy periwinkle), producing Vinca
alkaloids (vinblastine and vincristine)
MITOTIC SPINDLE INHIBITORS. II. Vincristine. I.
* vincristine (vinca alkaloid) binds to tubulin dimer →
microtubules “disaggregated” → block of growing cells in M phase (but toxic effects in G1 and S - phase also evident)
MITOTIC SPINDLE INHIBITORS. IIbis. Vincristine. Ibis.
* vinca alkaloids bind to tubulin dimers (at specific recognition site on
protein);
- tubulin - drug complex able to form paracrystaline aggregates → ↓
concentration of dimers and pushes equilibrium between growth and
shrinling of microtubules in favor of shrinking → cells treated with vinca
alkaloids loose ability to progress through mitosis correctly because of
poorly formed mitotic spindles → damaged cells then die
MITOTIC SPINDLE INHIBITORS. III. Vincristine. II.
* metabolized by liver (dose
adjustment with hepatic
dysfunction required);
- powerful vesicant (infiltration
treated by local heat and
infiltration of hyaluronidase);
* at clinically used iv doses,
frequent chronic neurotoxicity
(as glove - and - stocking
neuropathy)
MITOTIC SPINDLE INHIBITORS. IV. Vincristine. III.
* acute neurotoxicity also includes jaw pain, paralytic ileus,
urinary retention and syndrome of inappropriate antidiuretic
hormone secretion (no myelosuppression)
MITOTIC SPINDLE INHIBITORS. V. Vinblastine and vinorelbine
* vinblastine similar to vincristine, but more myelotoxic (with
more frequent thrombocytopenia and also mucositis and
stomatitis);
* vinorelbine: # in resistance patterns in comparison to
vincristine and vinblastine;
- it may be administered orally
MITOTIC SPINDLE INHIBITORS. I.
Drug
Examples of usual
Toxicity
doses
Indirect DNA - interacting agents
Interactions,
issues
Antimitotic agents
Vincristine
1 - 1.4 mg / m2 / wk
Vesicant
Marrow
Neurologic
GI: ileus / constipation;
Bladder toxicity; SIADH
Cardiovascular
Hepatic clearance
Dose reduction for bilirubin
> 1.5 mg / dL
Prophylactic bowel regimen
Vinblastine
6 - 8 mg / m2 / week
Vesicant
Marrow
Neurologic (less common
but similar spectrum to
other vincas)
Hypertension
Raynaud's
Hepatic clearance
Dose reduction as with
vincristine
Vinorelbine
15 - 30 mg / m2 / week
Vesicant, marrow
Allergic / bronchospasm
(immediate)
Dyspnea / cough (subacute)
Neurologic (less prominent
but similar spectrum to
other vincas)
Hepatic clearance
MITOTIC SPINDLE INHIBITORS
TAXANES
produced by plants of genus Taxus
MITOTIC SPINDLE INHIBITORS. VI. Taxanes
* taxanes include paclitaxel and docetaxel;
- # from vinca alkaloids (“disaggregating” microtubules),
taxanes “stabilize” microtubules against depolymerization
→ "stabilized" microtubules function abnormally (not able
to undergo normal dynamic changes of structure and
function necessary for cell cycle completion);
* among most broadly active antineoplastic agents for use
in solid tumors, with evidence of activity in ovarian, breast
and lung cancers and Kaposi's sarcoma;
- administered iv
MITOTIC SPINDLE INHIBITORS. VII. Paclitaxel
* paclitaxel requires Cremophor (polyethoxylated castor oil) containing vehicle responsible for hypersensitivity reactions;
- premedication with dexamethasone (20 mg orally or iv) 12
and 6 hrs before treatment, diphenhydramine (Benadryl®, 50
mg) and cimetidine (Tagamet®, 300 mg), both 30 min before
treatment, ↓ but does not eliminate risk of hypersensitivity
reactions to paclitaxel vehicle;
- beside hypersensitivity reactions, myelosuppression,
neurotoxicity (glove - and - stocking numbness) and
paresthesia;
- cardiac rhythm disturbances (most commonly asymptomatic
bradycardia and, much more rarely, varying degrees of heart
block) of poor clinical significance in most pts
MITOTIC SPINDLE INHIBITORS. VII. Paclitaxel
* protein - bound formulation of paclitaxel (called nab –
paclitaxel, Abraxane®) at least equivalent antineoplastic activity
and decreased risk of hypersensitivity reactions
MITOTIC SPINDLE INHIBITORS. VIII. Docetaxel
* docetaxel uses polysorbate 80 formulation, which can cause
fluid retention (from vascular leak syndrome);
- as paclitaxel, comparable degrees of myelosuppression and
neuropathy;
- hypersensitivity reactions (including bronchospasm, dyspnea,
and hypotension) less frequent (to some degree in up to 25% of
pts dexamethasone → premedication ± antihistamines frequently
used);
- rash (prominently as pruritic maculopapular rash affecting
forearms, but also associated with fingernail ridging, breakdown,
and skin discoloration) can occur;
- stomatitis somewhat more frequent than with paclitaxel
MITOTIC SPINDLE INHIBITORS. II.
Drug
Examples of
Toxicity
usual doses
Indirect DNA - interacting agents
Interactions,
issues
Antimitotic agents
135 – 175 mg / m2 / 24 - h
infusion
or 175 mg / m2/3 - h
infusion
or 140 mg / m2 / 96 - h
infusion
or 250 mg / m2 / 24 - h
infusion plus G-CSF
Hypersensitivity
Marrow
Mucositis
Alopecia
Sensory neuropathy
CV conduction
disturbance
Nausea - infrequent
Premedicate with
steroids, H1 and H2
blockers
Hepatic clearance
Dose reduction as with
vincas
NAB - paclitaxel
(protein bound)
260 mg / m2q 3vks
Neuropathy
Anemia
Neutropenia
Thrombocytopenia
Caution in hepatic
insufficiency
Docetaxel
100 mg / m2 / 1 hr
infusion q3 vks
Hypersensitivity
Fluid retention
syndrome
Marrow
Dermatologic
Sensory neuropathy
Nausea - infrequent
Some stomatitis
Premedicate with
steroids, H1 and H2
blockers
Paclitaxel
MITOTIC SPINDLE INHIBITORS. IX. Estramustine. I.
* estramustine (Estracyt) derivative of
estrogen (estradiol) with added nitrogen
mustard - carbamate ester moiety (→
→
alkylating antineoplastic agent with
estrogen - induced specificity);
- useful in neoplasms possessing
estrogen receptors (without evidence of
interaction with DNA);
- surprisingly, drug causes metaphase
arrest, by binding to microtubule associated proteins → abnormal
microtubule function
mechlorethamine
estradiol
estramustine
MITOTIC SPINDLE INHIBITORS. X. Estramustine. II.
* estramustine binds to estramustine - binding proteins
(EMBPs), notably present in prostate tumors tissue (→
→ used as
oral formulation in pts with prostate cancer);
- gastrointestinal and cardiovascular adverse effects related to
estrogen moiety in ~ 10% of pts, including worsened heart failure
and thromboembolic phenomena;
- gynecomastia and nipple tenderness also occur
MITOTIC SPINDLE INHIBITORS. III.
Drug
Examples of
Toxicity
Interactions,
usual doses
issues
Indirect DNA - interacting agents
Antimitotic agents
Estramustine
phosphate
14 mg / kg / d in 3 - 4
divided doses with
water > 2 h after meals
Avoid Ca2+ - rich foods
Nausea
Vomiting
Diarrhea
CHF
Thrombosis
Gynecomastia
CHF, congestive heart failure
-