Anticancer Chemotherapeutic Agents Flashcards
What is the mechanism of action of alkylating agents, in terms of cytoxicity
Damaged/chemically modified DNA is recognised by cellular machinery and the cell undergoes apoptosis. Alkylating agents purposefully alter the DNA of cancer cells. They bind to macromolecules in the cell (specifically DNA) to induce their effects.
Describe the properties of alkylating agents
A tertiary N with 2 chloroethane groups indicates that the molecule is bifunctional as the structure allows the molecule to react at two different sites. The molecules cross link the 2 sites and leads to strand breakage, impairing transcription and translation. The side effects of this type of chemotherapy are sever and varied, as they occur in different areas of the body and the DNA damage in the cells is not very well targeted
Explain the mechanism of action of Dactinomycin
Dactinomycin is an antibiotic that intercalates in the minor groove of the DNA strand, between C-G. This leads to a stable DNA-Dactinomycin complex, which interferes with DNA dependent RNA Polymerase and at high doses impairs synthesis. It can also cause single strand breaks by Top2 action or free radical generation. Its major toxicity is bone marrow depression, nausea, vomiting, diarrhoea, alopecia
Explain the mechanism of action of Doxorubicin
Intercalates non specifically between adjacent base pairs, binding to backbone and causing local uncoiling, blocking DNA and RNA synthesis. It also binds to cell membranes, altering transport processes. CYP450 catalyses the reduction of anthracyclines to semiquinone free radicals. They reduce O2 to form superoxides and H202 which mediate ss cuts. The generation of free radicals and association lipid peroxidation leads to irreversible dose-dependent cardiotoxicity when given in large doses, or for prolonged periods
Explain what is meant by an antimetabolite
An antimetabolite is a molecule that has a similar structure to normal cellular components and interferes with normal metabolic processes. They have a similar chemical structure to the substrates of the processes they inhibit
Explain the mechanism of action of Methotrexate
Methotrexate is a folate agonist, inhibiting dihydrofolate reductase, resulting in a reduction in tetrahydrofolate, which is a coenzyme for purine synthesis. This means there’s less DNA, RNA, protein biosynthesis which results in cell death
Explain the mechanism of action of Mercaptopurine
Mercaptopurine is converted into thio-IMP which blocks AMP, XMP, phosphoribosylamine synthesis required for purine ring biosynthesis. Thio-IMP is dehydrogenated to thio-GMP and di/tri phosphorylated which is then incorporated into DNA and RNA but the cell dies due to their function not being the same as a nucleotide
Explain the mechanism of action of 5-fluoracil
5-fluoracil enters the cell through carrier mediated transport and is converted to 5-fluorodeoxyuridine monophosphate, competing with deoxyuridine monophophate for thymidylate synthase. 5FdUMP is a pseudosubstrate and is trapped with enzyme and coenzyme in a tertiary complex which doesn’t release products, decreasing the availability of thymidine, and so decreasing DNA synthesis
How are microtubule inhibitors used as a cancer chemotherapy?
The micotubules are critical for cell function and division, as they make up the mitotic spindle. Targeting them is very effective in stopping cell division.
Explain the mechanism of action of Vincristine
Vincristine is a vinca alkaloid as it’s derived from the vinca rosea plant. It binds to tubulin in a GTP-dependent manner which stops polymerisation to form microtubules, therefore blocking mitosis in metaphase. Paracrystalline aggregates of tubulin dimers and the drug form. The spindle apparatus is dysfunctional and prevents chromosomal segregation and proliferation.
How are hormones and their antagonists used as chemotherapies?
Steroid hormone sensitive tumours are either hormone responsive (administration of a hormone causes regression) or hormone dependent (absence of a hormone causes regression) or both. Hormone treaatments are usually palliative, but high doses of glucocorticoids are cytotoxic to lymphomas.
Explain the mechanism of action of Prednisone
11-B-hydroxysteroid dehydrogenase reduces it to Prednisolone (it’s a pro-drug). It then binds to an intracellular receptor (steroid = lipid soluble) which dimerises, migrates to nucleus and interacts with DNA modifying gene transcription, inducing and inhibiting protein synthesis.
Explain the mechanism of action of estrogens
Ethinyl estradiol and diethylstilbestrol were used to treat prostate cancer, but now GnRH analogs are used because they have less adverse effects. Estrogens inhibit prostatic tissue growth as they block LH production which decreases androgen synthesis in testis, thereby slowing the growth of androgen dependent tumours.
Explain the mechanism of action of Tamoxifen
Tamoxifen binds to the estrogen receptor and the complex fails to induce estrogen responsive genes and RNA synthesis doesn’t ensue. This results in depletion of the estrogen receptor (down-regulation) and decreases the growth promoting effects of estrogen
How does cytotoxic resistance of cancer cells occur?
Cytotoxic resistance of cancer cells can be primary (present when the drug is given) or acquired (developed during treatment). Acquired resistance may result from adaptation of tumour cells, or mutation.
