Pharmacology 3620 Lecture Notes - Lecture 13: Vinca Alkaloid, Testicular Cancer, Paclitaxel
1 May 2018
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Lecture 013: Cancer Chemotherapy II
P-glycoprotein
● drugs exist to inhibit function of p-gp but none of them are useful in clinic
○ usually very toxic at therapeutic concentrations
Objectives
● Name examples of microtubule inhibitors, steroid drugs, and miscellaneous other
chemotherapy drugs
● Describe the mechanism of action and uses of taxol, tamoxifen, cisplatin and etoposide
General Drugs
1. Microtubule Inhibitors
● Widely used
● Cell cycle specific
○ Only kill cells in M-phase (mitosis)
● This is because during mitosis cell has to divide its duplicated DNA
○ Does it by anchoring one set of the chromosome to one side of the cell and the
other set of chromosome to the other side using microtubules
○ Thus microtubules are very important for replicated DNA to be properly
distributed to its daughter cells
● Type 1: Vinca Alkaloid
○ destabilizes MT by directly binding to it
○ vincristine and vinblastine
■ natural protein (extracted from periwinkle plants)
○ Recall: in metaphase chromosomes are held separate bt MT
○ Alkaloids inhibit with the microtubule ability to proliferate
■ Separation of chromosome does not occur because the cell does not
have enough microtubule
■ cell ends up not dividing
■ ends up as one large abnormal cell with extra chromosome which kills the
cell
○ Useful for most types of cancer
■ Leukemia, lymphoma
■ Testicular, lung cancer
○ M-phase specific
○ Tumor can become resistant to them via p-gp
○ IV administration
○ Hyperuricemia
■ Toxicity side effect
■ Dead cell release lots of degraded DNA
● excess purine is generated from the DNA
● Process is catalyzed by xanthine oxidase
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○ Thus it can be treated with allopurinol
● Type 2: Paclitaxel
○ Prevents depolymerization of microtubules once mitosis occurs
■ Binds to beta-tubulin and prevents prevents depolymerization
■ Need depolymerization to reassemble microtubule so mitosis can
progress
● Results in abnormal copies of DNA
● Induced cell death
○ Taxol
■ yew needles extract
■ natural product
○ very useful in ovarian and metastatic breast cancer
○ M-phase specific
○ Resistance mediated by p-gp
○ Can’t penetrate CNS
■ Can’t treat cancers in the brain
○ IV administration
○ Broad distribution
○ Hepatic metabolism, biliary excretion
○ Toxic effects
■ Neutropenia
● Increased infections
■ Alopecia
■ Hypersensitive
■ Pheripheal peuophates
2. Inorganic compounds
● Salts coordinated with platinum
○ Cisplatin
■ 2 amino and 2 chloride groups
○ Carboplatin
■ More carbon-based side chains
○ Platinum is free and available to interact with DNA
● non-cell cycle specific DNA modifying enzymes
● Platinum containing compounds
○ Platinum can form inter/intrastrand cross-links with the DNA and disrupt the
structure of the DNA
○ Inhibits DNA synthesis and RNA transcription
■ DNA and RNA polymerase “trip” because of the altered DNA
● Non cell-cycle specific
○ Cells have to transcribe RNA all the time, thus they effective all the time
● However they have greater toxicity during G1 and S phase
○ G1 phase:
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Drugs exist to inhibit function of p-gp but none of them are useful in clinic. Name examples of microtubule inhibitors, steroid drugs, and miscellaneous other chemotherapy drugs. Describe the mechanism of action and uses of taxol, tamoxifen, cisplatin and etoposide. This is because during mitosis cell has to divide its duplicated dna. Does it by anchoring one set of the chromosome to one side of the cell and the other set of chromosome to the other side using microtubules. Thus microtubules are very important for replicated dna to be properly distributed to its daughter cells. Destabilizes mt by directly binding to it. Recall: in metaphase chromosomes are held separate bt mt. Alkaloids inhibit with the microtubule ability to proliferate. Separation of chromosome does not occur because the cell does not have enough microtubule. Ends up as one large abnormal cell with extra chromosome which kills the cell. Tumor can become resistant to them via p-gp.
