intro to medical oncology – Flashcards
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| what is nowell's hypothesis? |
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| genetic instability inside the cell can lead to genetic abnormalities |
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| how can genetic abnormalities be aquired? |
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| through viral, environmental, chemotherapy and other means |
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| how does oncogenesis occur? |
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| a genetic abnormality is aquired, it expands to a clone, it loses contact inhibition (grows on other cells), cells build up and form a tumor, clones aquire additional abnormalities and expand to subclone which then becomes malignant through transformation and loses the ability for apoptosis/contact inhibition -> growth continues w/out any controls |
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| why are malignant genes selected for in cells? |
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| because of their ability to continue to populate |
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| how many steps does the "double hit" hypothesis really consist of |
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| it takes 7 genetic changes from a normal cell to a drug resistant metastasis. there can be some inherent abnormality within the cell – this alone is not enough to cause malignant transformation - however, if the cell is “hit” again or exposed to a second damage, in combination with the genetic condition, the cell will become cancerous. |
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| what is ultimately problematic about tumors? |
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| tumors continue to grow and take up metabolic resources, impinge on other structures and ultimately metastasize into other areas, if this last step could be controlled - pts could live like other pts with chronic diseases |
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| what are skipper's laws? |
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| the doubling time of proliferating cells is a constant (death results when malignant cells reach a critical level - usually after ~ 30 doubling times. the shorter your doubling time, the shorter your life expectancy) cell kill by chemotherapy follows 1st order kinetics (the % of cells killed at a given drug dose is constant, regardless of tumor size. a log-kill is one exponent-worth of tumor cell reduction: like a cell population at 10^9 being brought down to 10^8 is a 1 log-kill) |
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| what is the gompertzian growth curve? how do malignant cells get around this? |
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| a nonexponential growth pattern based on size of tumor and nutrient availability (growth will level off as blood supply/nutrient level drops off). malignant cells try to get around this through angiogenesis or makes VEGF receptors to aid in its growth, and also makeing VEGF for autostimulation. malignant cells will also be harder to treat due to lack of blood supply (how chemotherapy travels) and longer existence at G0 |
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| what is the goldie-coldman hypothesis? what does it mean in practice? |
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| a mathematical model that predicts that tumor cells mutate to a resistant phenotype at a rate dependent on their intrinsic genetic instability - according to this hypothesis, even the smallest detectable cancers contain at least 1 drug-resistant clone, and therefore the best chance of a cure is to use all effective chemotherapy drugs. in practice this = using 2+ non-cross-resistant chemotherapy drugs in alternating cycles |
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| what is an example of multidrug tx working? |
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| tumors down-regulate expression of carrier proteins that methotrexate uses and are thus resistant to it. cisplatin is then administered and when cells develop resistance to it, they are susceptible to methotrexate again |
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| what is stage 4 cancer? why is it so deadly? |
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| stage 4/metastatic cancer is where survival is very low (kills 90% of cancer patients) and other organ structures can become obstructed |
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| what is the multistep process of metastasis? |
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| invasion, intravasation (getting into blood/lymph circulation), survival in circulation, extravasion, and proliferation/angiogenesis at the new site (eventually this new tumor can metastasize) |
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| what is basically needed for cancer cells to grow? |
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| oxygen and blood supply |
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| is metastatic cancer curable? |
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| no |
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| what is the first step of systemic cancer therapy? |
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| set goals to either cure, prolong survival or provide palliative care |
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| when is primary/induction therapy used? |
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| primary/induction therapy is used when local therapy (sx/radiation) is inadequate and the disease has spread beyond local therapy's scope. it works to bring the disease back to a point where it can be locally treated or to where it is essentially gone. |
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| when is adjuvant therapy used? |
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| when disease has possibly spread outside the area of local control and there is a high risk of recurrence due to micrometastatic disease. |
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| what are the types of systemic therapy? |
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| cytotoxic (basically poison - hope is to kill more bad cells than good), hormonal (ex: tamoxifen w/breast CA), targeted (specific to the tumor like radioactive antigens), immunological (helps immune system fight off tumors like kidney CA) |
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| what are cytotoxic chemotherapeutic agents? |
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| antimetabolities, mitotic inhibitors, alkylating agents, antibiotics, and topoisomerase inhibitors |
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| what do antimetabolities do? are they specific to a cell cycle? |
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| antimetabolites are analogues of normal metabolites that affect RNA, DNA synthesis (folic acid, pyrimidine, cytidine and purine analogues) that work in the *S phase of the cell cycle: methotrexate, 5-fluorouracil and cytosine arabinoside are examples |
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| what are mitotic inhibitors? are they specific to a cell cycle? |
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| mitotic inhibitors bind to tubulin and arrest metaphase, some are mitotic spindle poisons stabilizing the microtubules/others disrupt the polymeration of microtubes. these work in the M phase (sometimes are only used with S phase). examples: vincristine, pacletaxel, docetaxel |
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| what are alkylating agents? are they specific to a cell cycle? |
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| these contribute alkyl groups to biological macromolecules such as DNA and cause cross-linking/strand breaks which the body attempts to repair, but cannot and dies. these are not specific to a cell cycle phase |
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| how do antibiotics kill tumor cells? are they specific to a cell cycle? |
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| antibiotics insert between base pairs and block synthesis of DNA, RNA or both (5-flurouracil affects both – these are the ones that are most effective) these are not specific to a cell cycle. examples; doxorubicin, bleomycin (“-rubicin” is an antibiotic) |
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| what are topoisomerase inhibitors? are they specific to a cell cycle? |
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| topoisomerase inhibitors inhibit enzymes that break and repair DNA strands, they work in the S phase and examples include etoposide and camptothecins |
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| why are cell cycle specific drugs given continously? |
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| the drug is given continuously to kill the cells in that cycle at that time (kill those in the S phase that were previously in the M phase and vice versa |
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| what are considerations for chemotherapy drugs given in combination? |
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| drug combinations are used to make sure mechanisms of action are different to prevent resistance, however care must be given to not combine toxicities or drugs have different metabolisms so they don't affect each other's concentrations |
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| what are benefits to giving alternating drug therapies? |
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| this can function as a 1-2 punch where drug A is given to affect cells a certain way, then adminstration is switched to drug B, once the cells targeted by drug A start coming back, drug A is re-administered |
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| what is the maximal tolerated dose (MTD)? |
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| this is tested by giving a drug to a small group of pts in increasing increments, and once you see the beginnings of toxicity you know to keep the dose below that and do not exceed it. in tx of pts, you want to get a dose that will give the greatest effects with least amount of side effects (safety index). |
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| how long should chemotherapy be given for? |
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| the shortest possible time, do not want high toxic doses for prolonged periods |
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| what is dose dense/intense therapy? |
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| instead of administering chemo, burning out WBCs and waiting 3-4 wks for them to return, chemo doses can be given now in shorter intervals because GCSF (granulocyte colony stimulating factor) can bring WBC counts faster and tx is more effective |
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| what is a toxicity associated with antracyclines? |
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| cardiac toxicity |
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| what is a toxicity associated with taxanes? |
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| neurological toxicity |
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| what is a toxicity associated with alkylating agents? |
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| secondary malignancy |
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| what is a toxicity associated with cisplatin? |
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| renal/neurotoxicity |
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| what is a toxicity associated with cyclophosphamide? |
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| hemorrhagic cystitis because of the drug metabolites |
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| how is toxicity prevented? |
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| anti-emetics for nausea, oral care for mouth sores, G-CSF to increase white cell count, hydration and diuresis to keep the flow going in kidney and bladder (remove irritation from bladder), cytoprotectants (ex: WR-2721 aka amifostine) drugs that protect normal cells from chemotherapy and/or radiation therapy |
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| what are some examples of endocrine therapies targeting CA? |
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| castration, SERMs (selective estrogen receptor modulators like tamoxifen), AI (aromatase inhibitors), anti-androgens, GnRH analogues (for prostate CA) |
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| what can be used for CA immunotherapy? |
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| IFN, IL-2 |
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| what are examples of targeted therapy? |
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| TKI, EGFR, anti-VEGF, proteosome inhibitors, mAb |
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| what does TKI do? |
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| TKIs (tyrosine kinase inhibitors) show a benefit in renal cell carcinomas |
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| what is EGFR used for? |
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| EGFR is as good, if not better, than classic chemo for certain tumors (limited) and can also be used after chemo for certain patients |
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| what is anti-VEGF used for? |
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| some tumors are highly dependent on VEGF, many studies show anti-VEGF treatments significantly increase survival |
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| what cancers are proteosome inhibitors used on? |
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| these are used on multiple myelomas and work very well |
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| what do mAb (monoclonal antibodies) do? |
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| mAbs like rituximab target lymphoma cells because they are abnormally marked cells and work exceptionally well |
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| how can genetic factors be used to fight cancer? |
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| genetic factors target the genome and will turn off promoter regions so the malignant cell will be converted back to normal because the genetic abnormality is known |
