Cancer Chemotherapy (Drugs) Flashcards
describe the toxicity of chemotherapy druges
- all chemotherapeutic agents are toic
- goal: selective toxicity
- toxicity to pathogen vs host is relative, not absolute
what are the different classes of chemotherapy drugs
- alkylating agents
- antimetabolites
- antitumor antibiotics
- microtubule poisons
- topoisomerase inhibitors
- target therapies: signal pathways, not proliferation
what is the mechanism of action, types of resistance, and adverse effects for alkylating agents? how do you know if these drugs are working? what is the dose-limiting toxic effect?
mechanism: covalently bind to/modify biological molecules - DNA; must be reactive and are CCNS (replicating cells are more sensitive); on DNA, are bifunctional in that they can make pyrimidine dimers or cross link DNA
* covalent modification is key*
resistance: drug cannot get into cell (impermeable), pump drug out, increased DNA repair, no apoptosis (no p53), and may have alternate targets for drug (Glutathione)
adverse effects: secondary malignancy (normal cells will get mutations), other rapidly growing cells are targeted (bone marrow, GI, spermatogenesis)
know if they are working by looking at CBC - should see decreased leukocytes, platelets and hematocrit
dose-limiting toxic effect: decreased leukocytes and platelets; given in cycles -> will give as much as the patient can tolerate and then wait for the patient to recover
what is the mechanism of action of antimetabolites? what are the three main types (not drugs, but types)
analog of a normal component in the target cell and it competes with this normal component by entering into the normal metabolic pathway and either blocking or altering the pathway
types:
folate analogs
purine analogs
pyrimidine analogs
what are antitumor antibiotics? how do they work and how are they given to patients? anything special?
they block access to/function of DNA/RNA but not through alkylation
given intravenously and there are unique toxicities associated with these compounds
most are produced by microbes
how do microtubule poisons work?
by causing metaphase arrest either via stabilization of microtubules or inhibition of microtubules
what do the current target pathway drugs target? give examples of these targets
target signaling pathways driving proliferation, not specific characteristics of proliferation
- inhibit agonist synthesis or release
- agonist scavengers
- receptor antagonists
- anti-receptor MAb
- tyrosine kinase inhibitors
also hormonal therapy - acivity requires functional hormone receptor
- androgens: prostate
- estrogens: breast, uterus, cervix
- corticosteroids: leukocytes, lymphocytes
mechlorethamine
- alkylating agent
- IV only (in arterial supply to tumor)
- short half-life
- adverse effects: nausea, vomiting, decreased CBC (min levels 10-12 days after tx)
- primary use: hodgkin’s disease
cyclophosphamide
- alkylating agent
- IV or oral
- is a pro-drug; metabolized in liver to active form
- adverse effects: nausea, vomiting, bone marrow depression, alopecia (hair loss), sterile hemorrhagic cystitis (no infection, blood in urine - caused by acrolein from metabolism)
- special: protect from sterile hemorrhagic cystitis by forced hydration or Mesna (thiol which reacts with acrolein)
cis-platin
- alkylating agent…platinum complex
- bifunctional: cross-links DNA; blocks DNA synthesis
- IV (cleared in urine)
- relatively non-toxic to bone marrow
- adverse effects: severe nausea and vomiting
- special: renal toxicity is dose-limiting…ensure adequate hydration; also, use HT3 antagonists (ondansetron) to help with nausea…block serotonin receptor (but only works on 70% of patients)
methotrexate
- antimetabolite
- competes with folic acid by binding to and inhibiting diydrofolate reductase (DHFR) (this enzyme converts the inactive form of folic acid to the active form)
- this blocks DNA synthesis because U cannot be converted to T (ie blocks production of bases for DNA synthesis)
- greater accumulation in tumor cells
- orally, IV, intrathecally (spinal cord because cannot pass BBB)
- excreted in urine
- adverse effects: bone marrow, GI
- resistance: decreased drug accumulation, amplified DHFR, altered DHFR, pumped out by MDR1 (ATP driven)
- may give a high dose followed by “rescue” with citrovorin or leucovorin
purine analogues (drug and mechanism)
- drugs: 6-Mercaptopurine (inhibits AMP and GMP synthesis) and 6-Thioguanine (incorporated into RNA and DNA)
- inhibit synthesis of essential precurosrs of DNA (affects guanine)
- oral
- inactivated by thiopurine methyltransferase (TPMT)…if patient does not have enough of this, fatal myelosuppression will occur
- requires purine salvage pathway: hprt
- competes with normal bases to block/alter nucleic acid synthesis
- adverse effects: well tolerated, bone marrow affected only at high doses
- resistance: decrease in hprt activity or increase in alkaline phosphatase
pyrimidine analogues (drug and mechanism)
- drugs: 5-Flouorouracil (5-FU…inhibits thymidylate synthase in its FdUMP form) and Gemcitabine (cytosine analogue; inhibits polymerase and chain terminator)
- inhibits synthesis of essential precursors of DNA
- adverse effects: bone marrow, GI (far more toxic than purines)
- in order for 5-FU to work, need to have folinic acid in the active site of thymidylate synthase
anthracyclines
- antitumor antibiotic
- drugs: doxorubicin and daunorubicin
- intercalate into DNA, which blocks topoisomerase II, inhibits DNA/RNA synthesis and causes strand breaks
- generates free radicals -> causes cardiotoxicity because free radicals target cardiomyocyte mitochondria…function of cumulative dose and can minimize this effect by: Dexrazoxane
- IV
- metabolized in liver
- adverse effect: bone marrow suppression, GI distress, severe alopecia (hair loss)
Bleomycin
- antitumor antibiotic
- CCS: active in G2
- binds to DNA, generates free radicals, causes strand breaks
- adverse effects: pulmonary fibrosis, hypersensitivity, cutaneous reactions
vincas
- microtubule poisons: inhibits/reverses tubulin polymerization, disrupts mitotic spindles (mmicrotubules)
- causes metaphase arrest
- IV
- biliary excretion
types. ..
1. vinblastine: nausea and vomiting, alopecia, bone marrow depression
2. vincristine: less toxic to bone marrow, no nausea and vomiting; but causes peripheral neuropathy so only use for a short time
taxanes
- microtubule poisons: stabilizes the mt and blocks progression through mitosis (mt cannot depolymerize)
- IV
- acute hypersensitivity, nausea, delayed bone marrow suppression, some neuropathy
- drugs: paclitaxel and docetaxel
irinotecan
- topoisomerase inhibitor: camptothecins
- pro drug; converted to active SN-38 by esterase
- SN-38 inhibits topo I and causes nausea, vomiting, diarrhea (dose-limiting effect), bone marrow suppression
- UGT1A1 is an enzyme that contributes to hematological toxicity of drug…inactivates SN-38
what do polymorphisms in UGT1A1 cause?
- increased sensitivity to irinotecan
- Crigler-Najjar syndrome
- Gilbert’s disease
- Hyperbilirubinemia
aromatase inhibitor
- targeted hormone therapy
- blocks conversion of androgens to estrogens; use in post-menopausal women
- drugs: anastrazole, letrozole
- treatment for primary ER+ and metastatic breast cancer
- adverse effects: nausea, headache, fatigue, hot flushes
SERM
- selective estrogen receptor antagonists: competing ligands for ER
- tamoxifen…ER antagonist in breast but ER agonist in endometrium; orally; activated by CYP2D6 to a more potent form
- treatmetn for ER+ primary and metastatic breast cancer
- adverse effects: nausea, hot flushes, vaginal bleeding
androgen receptor antagonists
- diminish androgen effects by binding to AR
- drug: flutamide
- oral
- used with radiation for prostate cancer
- adverse effects: nausea, hot flushes, transient hepatic effects
trastuzumab
- biological antineoplastic agents
- monoclonal antibody against HER2/neu oncogene product
- does not cross BBB
- EGFR receptor amplified in ~25% of breast cancers, poor prognosis
- IV
- adverse reactions: hypersensitivity, cardiomyopathy, infusion reactions
imatinib
- tyrosine kinase inhibitors
- inhibits BCR-ABL and other tyr kinases -> specific for chronic myelogenous leukemia (CML)
- also blocks kit kinase in GI stromal tumors (GIST)
- myelosuppressive
- edema and fluid retention, hepatotoxicity
dasatinib
- overcomes imatinib resistance
- is a second generation BCR-ABL inhibitor -> tyrosine kinase inhibitor
gefitinib
- inhibits EGFR tyrosine kinase
- oral
- works best with non-small cell lung cancer, asian women who do not smoke
- all about the genetics of the tumor
- may cause fever, dyspnea
what is the importance of STI (selective tyrosine inhibitors) and when does this treatment stop?
- transforms cancer from a “curable” disease to a “manageable” disease
- focuses on the genetics of the tumor
- treatment continues until the tumor gains resistance, the patient dies, or the patient chooses to discontinue the drug
pertuzumab
HER2/neu + breast cancer tumor; inhibition of ligand-dependent signaling (so the ligand is there and pertuzumab will inhibit signaling); inhibited formation of ligand-dependent heterodimers
lapatinib
inhibition of ligand-dependent and ligand-independent signaling for HER2/neu + breast cancer tumor
herceptin
used in HER2/neu + treatment; attaches to HER2 and blocks dimerization
tykerb
tyrosine kinase inhibitor
what are the alkylating agents?
cyclophosphamide, mechlorethamine, cis-platin
antimetabolites
5-FU, gemcitabine, 6-mercaptopurine, methotrexate, thioguanine
antitumor antibodies
bleomycin, daunorubicin, doxorubicin
mt poisons
docetaxel, paclitaxel, vinblastine, vincristine
topo inhibitors
irinotecan
targeted therapies - hormonal agents
anastraxole, letrozole, flutamide, tamoxifen
targeted therapies - biologicals
trastuzamab, gefitinib, imatinib
targeted therapies - tyrosine kinase inhibitors
dasatinib
ancillary drugs
- dexrazoxane - used with anthracyclines to help stop free radical damage to mitochondria in cardiomyocytes
- erythropoietin - used to help stimulate RBC production/help the bone marrow
- GM-CSF - used to help stimulate granulocyte and macrophage production
- Mesna - used to help treat uterine toxicity when given cyclophosphamide
- ondansetron - HT3 used to help with nausea, especially with cis-platin
tolvaptin
blocks the vasopressin receptor which will decrease the [cAMP] in the cell; patients are EXTREMELY thirsty
