Download Chapter 49 Antineoplastic Drugs

Chapter 49 Antineoplastic
Drugs
Department of pharmacology
Liu xiaokang(刘小康）
2010,3
Categories:
• 1) Antimetabolites: a) Folic Acid Analogs
(Methotrexate, MTX). b) Pyrimidine analogs
(Fluorouracil,
5-FU;
Fluorodeoxyuridine;
Cytarabine).
d)
Purine
analogs
(6Mercaptopurine, 6-MP; 6-Thioguanine, 6-TG).
• 2) Alkylating agents: Nitrogen mustards;
Cyclophosphamide; Thiotepa.
• 3) Natural products: Vinca alkaloids
(Vincristine; Vinblastine; Vinorelbine); Paclitaxel
(Taxol® )
• 4) Antiumor antibiotics: Anthracyclines
(Doxorubicin hydrochloride,
Daunorubicin, Bleomycin)
• 5) Miscellaneous agents: Cisplatin;
Carboplatin; Asparaginase; Hydroxyurea;
Corticosteroid
Mechanisms:
• Biological mechanism:
• (1) Cell cycle:
• a) Gap 1 (G1 phase). b) DNA synthesis (S
phase). c) Gap 2 (G2 phase). d) Mitosis
(M phase). G0 is a resting phase in which
the cells are not prolifering.
• (2) Cell cycle nonspecific agents
(CCNSA):
• Kill proliferating cells preferentially, act
on cells at all phases.
• (3) Cell cycle specific agents (CCSA):
• Act at specific phase of the cell cycle.
• Biochemic mechanism:
• 1) Interfere nucleotide synthesis.
• 2) Impact the structure and function of
DNA
• 3) Interfere transcription and block RNA
synthesis.
• 4) Interfere protein synthesis and
functions.
• 5) Change hormone lever.
Resistance mechanism
• (1) Defective activation:
Cyclophosphamide requires
metabolic activation, Methotrexate
conversion to more active MTXpolyglutamate in cells
• (2) Increased inactivation: e.g.,
aldehyde dehydrogenase converse
cyclophosphamide to inactive metabolite.
• (3) Altered nucleotide pools: Can
occur with antimetabolites.
• (4) Altered DNA repair: Repair
mechanisms increased, i.e., ability to
remove cross-links, Affect the action of
bleomycin and other DNA-directed drugs
• (5) Altered target: Less affinity for
drug, Methotrexate (Dihydrofolate
reductase changes ).
• (6) Decreased target: decreased
topoisomerase II, e.g., etoposide
• (7) Gene amplification: Methotrexate
(MTX) increase dihydrofolate reductase,
hence Requires more MTX to block
• (8) Decreased accumulation: Decreased
uptake (Methotrexate -- carrier protein
decreases). Increased Efflux (Multidrug
Resistance, P-Glycoprotein (gP-170) in
membrane, pumps drug out)
Commonly used antineoplastic
drugs
• Antimetabolites
• Group Characteristics:
• (1) Resemble NORMAL substrates.
• (2) Most inhibit DNA synthesis.
• (3) Some inhibit RNA synthesis and/or
function. (4) Bone Marrow cell
replication is profoundly inhibited.
• (5) GI toxicity great with some drugs.
• (6) Highly cell cycle specific, also "phase
specific", e.g., S or M phase
Methotrexate (MTX)
• Structure:
• Mechanism of action:
• (1) Folic Acid Analogue, Carrier
transport into cell. (2) Binds strongly to
DHFR to deplete THF, Decreases 1carbon transfers in Purine synthesis,
Decreases [1-C-THF] intracellular which
decreases dUMP dTMP, Therefore,
decreases NUCLEIC ACID synthesis.
• Adverse effects:
• (1) Dose limiting: a) Myelosuppression
(Thrombocytopenia and Leukopenia,
Nadirs 7-10 days after Rx, Recovery 1421 days). b) GI toxicity (Oral mucositis is
early sign of GI toxicity, Severe mucositis,
Small bowel ulceration & bleeding,
Diarrhea -- requires cessation to prevent
perforation of gut )
• (2) Nephrotoxicity: Conventional doses,
infrequent toxicity; High doses, toxicity
can be severe
• (3) Immunosuppression.
• (4) Hepatotoxicity.
• Clinical Uses:
• Broad range. Well established: (1) Acute
Lymphoblastic Leukemia of childhood. (2)
Choriocarcinoma. (3) Cancers of breast,
bladder, and head & neck. (4) Useful in
non-Hodgkin's lymphomas
Flurouracil (5-FU)
• Structure:
• Mechanism of action:
• (1) Activated by conversion to nucleotide
• (2) Inhibits DNA synthesis: Inhibition of
Thymidylate
synthase—the
most
important mechanism of action (MOA) in
rapidly growing tumors (?)
• (3) 5-FU Incorporated into RNA:
Interfere with RNA processing - All types,
May be most important MOA in slowly
growing tumors.
• Adverse effects:
• (1) Dose limiting: a) Bone marrow -- esp.
with bolus administration. Leukopenia &
Thrombocytopenia (nadir 9-14 days after
5 days of Rx, recovery by day 21). b) GI
Toxicity -- esp. with infusion
administration. usually Stomatitis &
Diarrhea 4-7 days after Rx.
• (2) Effect of route and schedule on
adverse effects:
• IV bolus: myelosuppression is dominant;
Prolonged Rx, may cause megaloblastic
anemia
• Continuous IV Infusion: Frequently
produce, stomatitis, nausea, vomiting,
and diarrhea; Hepatotoxicity (elevated
transaminases); myelosuppression less
common
• (3) Effect of peak 5-FU concentration:
• Acute, reversible cerebellar syndrome:
somnolence, ataxia of trunk or
extremities, unsteady gait, slurred speech,
nystagmus
• (4) Other adverse effects:
• Hyperpigmentation of skin is frequent
and may be accompanied by
photosensitivity; Toxic effect of radiation
to skin may be enhanced; Alopecia, acute
and chronic conjunctivitis, and nail
changes may be observed.
• Clinical Use of 5-FU:
• (1) Single agent: Palliative in advanced
colorectal carcinoma
• (2) Combination: Breast cancer;
Carcinomas of ovary, stomach, pancreas
• (3) Sequential MTX + 5-FU: Head and
neck cancer
Alkylating Agents
• Nitrogen mustard
• General view:
• (1) Developed from mustard war gases of
Word War I which were highly reactive
vesicants.
• (2) First chemicals used for cancer Rx.
• (3) Not cell cycle specific, but still more
active in dividing tissues.
• (4)"Radiomimetic" -- action on DNA
resembles radiation.
• Mechanism of action:
• (1) Highly reactive: Form covalent bonds
with NDA, RNA and protein
• (2) Consequences: a) DNA-DNA strand
and DNA-Protein cross-links. b)
Misreading of genetic code. c) DNA
Chain breaks
• Adverse effects of alkylating agents:
• (1) More toxic to bone marrow and gut
than to liver and kidney, etc. (2)
Infertility to both males and females. (3)
Mutagenic. (4) Carcinogenic.
• Tumor resistance:
• Develops slowly & may require several
genetic / biochemical changes
• Clinical Uses:
• Wide spectrum; Lymphoreticular tissue
tumors; Limited activity against
sarcomas.
Cyclosphosphamide
• Mechanism of action:
• Hepatic cytochrome P-450 system, enzymes
phosphatase and phosphamidase are primary
activators (hydrolyze P-N bond) to
intermediate, aldophosphamide, which
nonenzymatically breaks down to -Phosphoramide mustard (bifunctional) &
Acrolein
• Pharmacokinetics:
• Oral bioavailability = 90-100%, IV
injection no local irritation
• Half-life -- cyclophosphamide -- 3-10 h;
aldophosphamide
-1.6
h;
phosphoramide mustard -- 8.7 h.
• Most metabolized-- < 14% unchanged in
urine.
• Clinical Applications:
• (1) Most widely used alkylating agent, in
part due to availability of oral route
• (2) Active on lymphoproliferative diseases,
e.g., Hodgkin's disease and Chronic
lymphocytic leukemia
• (3) Significant activity vs multiple
myeloma & ovarian, breast, small cell
lung carcinoma
• (4) Many combinations.
• Adverse effects:
• (1) Bone marrow suppression, most
important
leukopenia
and
thrombocytopenia
• (1) Nausea and vomiting said to be rare
• (3) Sterile necrotizing hemorrhagic
cystitis. Acrolein is probable cause. To
minimize cyctitis--high water intake and
take in AM
Natural Products
• Vinca Alkaloids
• Vincristine sulfate and Vinblastine sulfate
• Mechanism of action:
• (1) Uptake by energy dependent carrier
• (2) Bind to tubulin in microtubules to
cause their dissolution. Contrast to Taxol
which stabilizes tubules.
• (3) No cross resistance between
vincristine and vinblastine
• Uses:
• (1) Drug of choice for childhood
leukemias
in
combination
with
prednisone
• (2) Used for lymphoreticular neoplasms,
carcinomas, and sarcomas
• Adverse effects:
• (1) Severe vesicant. Must be careful of IV
equipment to avoid slough.
• (2) Neurotoxicity: a) Mild sensory
neuropathy with sensory impairment and
paresthesia--Keep Rx. b) Severe
paresthesias, loss of reflexes, ataxia, and
muscle wasting-- stop Rx. c) Constipation
and abdominal pain - take laxatives. e)
Less hematologic effects than many other
cytotoxic drugs.
Antitumor Antibiotics
• General characteristics:
• (1) All interact with DNA and/or RNA,
but may also interact with other cellular
substituents.
• (2) Schedule dependence: LESS "phasespecific" than antimetabolites.
• (3) Tissue necrosis is only generalizable
toxicity.
• (4)All IV except bleomycin
• Doxorubicin(AdriamycinR)
• Mechanism of action:
• (1) DNA topoisomerase II inhibitor:
Crucial to DNA replication and
transcription.
• (2) Traditional explanations of MOA: a)
intercalates between base pairs of DNA
and inhibits DNA-dependent RNA
synthesis. b) Generates free radicals that
cause membrane damage and DNA
strand breaks.
• Resistance:
• (1) Alterations in Topoisomerase II
activity.
• (2) Increased inactivation of radicals: a)
Increase
in
glutathione-dependent
enzymes, e.g., glutathione-peroxidase. b)
Altered NADPH contents.
• (3) Increase drug efflux: a) Multi-drug
resistance (MDR). b) P-glycoprotein (gP170) pump is product of mdr gene
• Adverse effects:
• Three categories of toxicity: a) Local
toxicities. b) Acute toxicities. c) Chronic
toxicity
• (1) Local Toxicity -- Extravasation
• Extravasation -- DON'T! Severe local
tissue necrosis to point of damaging
underlying structures; If occurs, treat
immediately: Remove blood from IV line;
Apply ice, steroid cream; Locally adm.
sodium bicarbonate and hydrocortisone.
• (2) Local Toxicity -- Radiation Recall
• Interaction of doxorubicin and radiation
in some tissues to produce enhanced
reactions.
• Reactions include: a) Skin: ulceration
and necrosis. b) Pulmonary: fibrosis and
sloughing of esophageal mucosa. c) Heart,
and intestinal mucosa may also be
affected
• (3) Acute Toxicities
• a) Hematologic: Leukopenia with nadir
7-10 days; recovery typically by 21 days;
Thrombocytopenia and anemia less
common
• b) If give too fast: "Histamine-release"
syndrome; Cardiac arrest preceded by
ECG changes
• (4) Chronic Toxicities
• a) Cardiomyopathy and congestive heart
failure: require cessation of Rx after
cumulative dose of 550 to 600 mg/m2;
must maintain record of total dose.
• Clinical Indications:
• (1) Broad spectrum anti-cancer activity.
• (2) Hodgkin's disease, non-Hodgkin's
lymphomas, sarcomas, acute leukemia,
and breast, lung, and ovarian carcinomas
all responsive
• (3) Activity observed in bladder tumors,
and carcinomas of prostate, thyroid,
endometrium, head and neck, and other
solid tumors
•
(The end)