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14 Cards in this Set
- Front
- Back
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What are calcineurin inhibitors and what do they do?
What are they used for? |
The calcineurin inhibitors (Cyclosporine & Tacrolimus) target specific steps in the activation of immune cells
-cyclosporine specifically inhibits early T cell activation & prevents synthesis of several cytokines, in particular IL02 -without stimulation of IL-2, T-cell proliferation is inhibited, and T-cell cytotoxic activity is reduced -cyclosporine is not cytotoxic or myelotoxic and is SPECIFIC for lymphocytes -this spares rapidly dividing cells, and leaves non-specific defense mechanisms functional Cyclosporine is USED FOR: -immune-mediated haemolytic anemia, for perianal fistulae, atopy and for opthalmic conditions |
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What are the 4 characteristics that cancer cells manifest?
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-uncontrolled proliferation, dedifferentiation, loss of function, invasiveness & metastasis
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How is the cell cycle controlled?
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-it is regulated by growth factors, cyclins, cyclin dependent kinases, & negative forces (e.g. brakes) such as p53 gene that halts the cycle at G1/S and triggers apoptosis if the cell is damaged & retinoblastoma (Rb) gne
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How does cancer arise?
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-genetic lesions such as the activation of proto-oncogenes to oncogenes (mutation of the normal genes controlling cell division) or inactivation of tumour suppressor genes, e.g. p53
-if DNA is damaged, protein products of p53 gene accumulate and arrest DNA replication -allows time for repair or if repair fails, p53 activity triggers cell suicide by apoptosis -p53 may be altered or inactivated by viral or other host proteins, and affected cells cannot stop the abnormal DNA from replicating, mutations and other chromosomal abnormalities then accumulate leading to cancer -mutation in p53 are the most commonly found mutations in cancer cells |
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What are the general principles of cancer therapy?
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-effective cancer chemotherapy depends on the concept of selective toxicity ie. that the toxicity to the tumor cell is greater than the toxicity to normal cells
-neoplasms that are most susceptible to chemotherapy are those with large growth fraction ie. higher percentage of cells in the process of division -cells that rapidly proliferate ie. bone marrow, hair follicles, intestinal cells are susceptible to damage -most chemotherapeutic agents cause damage to DNA -damaged cells that cross the G1/S boundary will undergo apoptosis if the p53 gene is in tact -if p53 is mutated or inactivated so apoptosis can not occur, the mutated/damaged cells can go through S phase and emerge as a drug resistant population |
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Why does resistance to anti-cancer drugs occur?
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-can be primary or acquired (developed during treatment)
-acquired can be due to adaptation of the tumor cell or to mutation, which leads to development of a population of cells less affected by the drug, and therefore with a selective advantage MECHANISM OF RESISTANCE: ❤Decreased accumulation of drug in cells due to expression of drug transport protein, that expels many structurally dissimilar drugs from the cytoplasm ❤decreased uptake of drug into the cell ❤Altered metabolism of the drug so that drugs do not enter the pathways where they would normally have their effects |
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Why do we treat with combinations of several anti-cancer drugs? Why do we give drugs in larger doses?
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-it increases the cytotoxicity to cancer cells, without necessarily increasing general toxicity
-drugs are often given in large doses intermittently (intervals of 2-3 weeks) rather than in small doses continuously -this allows time for bone marrow to recover -it has also been shown that the same total dose in one or more larger doses is more effective than multiple small doses |
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What are the types of cancer drugs we have?
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CYTOTOXIC AGENTS:
❤alkylating agents & related compounds - act by forming covalent bonds with DNA & thus impeding DNA replication (e.g. nitrogen mustards, cyclophosphamide, chlorambucil) ❤antimetabolites, that block or subvert one of the pathways involved in DNA synthesis (e.g. methotrexate, 5-fluorouracil, azathioprine) ❤cytotoxic antibiotics - ie. substances of microbial origin that prevent mammalian cell division ❤plant derivatives (vinca alkaloids, taxanes) that specifically affect microtubule function and hence the formation of the mitotic spindle HORMONES: -particularly steroids, prednisolone, estrogen & androgen antagonists MISCELLANEOUS AGENTS -e.g. cisplatin, mitotane, L-aspariginase |
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What do Alkylating agents do? What are some examples?
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-act by forming covalent bonds with DNA
-causes impediment in DNA replication & DNA damage leading to DEATH by apoptosis ❤Cyclophosphamide - MC used alkylating agens -has a pronounced effect on lymphocytes and can be used as an immunosuppressant SIDE EFFECTS: myelosuppression, with leukopenia 7-14 days following administration, as well as nausea & vomiting, and hemorrhagic cystitis ❤Chlorambucil - used in dogs & NOT CATS ❤Cisplatin - not an alkylating agent BUT acts by causing intra-strand linking in DNA, and so inhibits DNA replication & promotes apoptosis in a similar way |
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What do anti-metabolites do? What are some examples
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-block or subvert pathways in DNA synthesis, by a variety of pathways that do not involve inhibition of DNA precursor formation, or synthesis of "corrupted" non-replicative DNA
❤Folate antagonists - folate is essential or synthesis of purine nucleotides & thymidylate, which in turn are essential for DNA synthesis and cell division e.g. Methotrexate is a folate antagonist used to treat leukemias and also autoimmune diseases ❤Pyrimidine analogues - e.g. 5-Fluorouracil is incorporated into tymidine nucleotide precursor but cannot form proper nucleotide, and so inhibits DNA synthesis but not RNA or protein syntheis ❤Purine analogues have a similar mechanism of action leading to formation of "corrupted" purine nucleotide precursors e.g. Azathiopurine is used as an immunosuppressant (particularly for auto-immune disease e.g. immune-mediated hemolytic anemia, immune mediated thrombocytopaenia) in combination therapy with prednisolone TOXIC EFFECTS: myelosuppression, acute pancreatitis & hepatotoxicity |
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What do cytotoxic antibiotics do?
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-anti-tumor antibiotics that produce their effects mainly by direct action on DNA
e.g. doxirubicin |
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What do plant derivatives do in anticancer therapy? What are some examples?
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❤The vinca alkaloids e.g. vincristine, vinblastin
-these drugs act by binding to tubulin, and preventing microtubule formation and hence spindle formation in mitosing cells thereby arresting cell division in metaphase -non-toxic, but some neurotoxicity ❤Taxanes e.g. paclitaxel (taxol) -act on microtubules in a different way to "freeze" the microtubule and prevent completion of mitosis |
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What do hormones do in anti-cancer therapy? What are some examples?
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-hormones or their antagonists are used in hormone sensitive tumours:
❤glucocorticoids for leukemias and lymphomas ❤tamoxifen (anti-estrogen) for breast tumors in humans ❤anti-androgens (delmadinone) for prostate and anal gland tumors in male dogs |
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What are some general considerations we must have in using anti-cancer drugs?
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-solutions must be prepared in a biological safety cabinet with protective clothing etc.
-doses are calculated according to the surface area of the animal -anti-neoplastic drugs carry significant EH&S safety risks (avoid breaking tablets & avoid extravasation from site of venipuncture) -must consider health of animal, benefits, side effects, and circumstances of owner |
