Anti-tumor agents Flashcards
Understand differences and purposes of different kinds of chemotherapy- adjuvant, neoadjuvant and primary chemotherapy.
ADJUVANT - after local treatment, trying to kill micrometastases.
NEOADJUVANT - before localized treatment, trying to make that treatment more effective and less damaging.
PRIMARY - on its own with no other therapy in a few cases curative, more often for palliation of symptoms in patients with advanced disease.
Understand major differences between “targeted therapies” and conventional cytotoxics.
Conventional agents damage normal cells as well as tumor cells - therapeutic window is largely based on tumor cells being closer to their apoptotic threshold, MTD relevant for conventional agents less so for targeted agents, which are usually less toxic, resistance mechanisms different.
TARGETED goes after a specific kinase or receptor, for example
Remember: conventional cytotoxics hit specific targets (e.g. Topoisomerase/DNA) just like “targeted” agents do- difference is that with the newer “targeted” agents we aim to hit a target that is different/faulty in tumor cells but not normal cells.
Understand basis for combining anti-tumor agents.
Combine agents that work to at least some extent on their own, avoid overlapping toxicities, use drugs at optimal doses, keep treatment-free schedules as short as possible. Basically: suppress natural selection (ability for tumor to get around treatment)
What are the ~7 classes of chemo drugs?
DNA damaging agents toposiomerase interacting agents Antimetabolites [Anti]microtubule interacting agents hormonal agents antibodies kinase inhibitors.
Mechanism, resistance, toxicity for DNA damaging agents
Mechanism: crosslink DNA –> cell sees damage –> apoptosis
Resistance: deactivate alkylating agent, use repair mechanism to cut out problem, or decreased drug uptake / increase efflux.
Toxicity: immune dysfunction, GI & gonad probs, alopecia, carcinogenesis
Antimetabolite
Mechanism: Reversible, competitive inhibitor of enzyme in critical pathway (then make toxic metabolite)
Resistance: Lower capacity to make active form of the drug, ramp up enzyme production, make mutant enzyme w/ different binding affinity
Toxicity: Myelosuppression, GI toxicity (damage to rapidly growing normal cells), renal toxicity in patients with poor kidney function. Associated with excretion of the drug by kidney. Hepatotoxicity, Neurotoxicity, Teratogenicity (malformation of embryo)
Topoisomerase
Mechanism: prevent re-ligation of strands after nicks/cuts
Resistance: influx/efflux, make enzyme that doesn’t bind drug as well
Toxicity: MYELOSUPPRESSION, Cardiotoxicity, secondary malignancies (esp AML)
Anti-MT
Mechanism: stabilize (prevent depolymeraztion, like in mitosis); sometimes destabilize
Resistance: influx/efflux, alter tubulin binding
Toxicity: Neurotoxicity (damage neurons), myelosuppression, neutropenia
Hormonal agents
Mechanism: block receptor (or downstream effect)
Resistance: mutate receptor to dec binding, activate pathway in other ways
Toxicity: associated with altered steroid hormone signaling- e.g. hot flashes, decreased bone density in women treated with tamoxifen. Gynecomastia in men treated with anti-androgens.
Antibodies
Mechanism: inhibit function of target (block stimulation of receptor), mediate cell toxicity by NKs, help deliver drug
Resistance: ?
Toxicity?
Kinase inhibitor
Mechanism: target a specific kinase that is activated in cancer cell (bind active site)
Resistance: Pump drug out, sequester else where (doesn’t ge tto cells), activate other pathways, overexpress target, inhibitor insensitive alleles.
Toxicity:
Thorburn’s generalities
Some resistance mechanisms generally applicable- e.g. drug efflux through transporters, some specific to agent- e.g. mutations in drug target, activation of repair mechanisms, other ways to activate steroid receptors.
Many drugs have similar toxicities- usually associated with damage to fast growing cells- GI toxicity, myelosuppression. Specific toxicities depend upon mechanism of action- e.g. neurotoxicity associated with microtubule-interacting agents.
Common mechanisms of resistance
Reduced uptake of the drug in tumor cells/ increased drug efflux- can lead to multiple drug resistance (MDR).
Reduced activity of apoptosis machinery.
Mutations alter cellular target of the drug- e.g. kinase inhibitors, DHFR resistance to MTX.
Increased repair of the cellular damage- e.g. after DNA damage
A sub-population of cells may be resistant to the drug but capable of tumor regeneration- tumor stem cells
Remember: cancer cells are genetically unstable AND under strong selective pressure to evolve to become resistant to the treatment
