Cancer Chemotherapy Flashcards
What are cell cycle non-specific (CCNS) drugs?
anticancer agent that acts on tumor cells when they are traversing the cell cycle and when they are in the resting G0 phase
What are cell cycle-specific (CCS) drugs?
anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the resting G0 phase
What is the growth fraction?
proportion of cells in a tumor population that are actively dividing
What is the log-kill hypothesis?
concept used in cancer chemotherapy to mean that anticancer drugs kill a fixed proportion of tumor cell population, not a fixed number of tumor cells (e.g. a 1-log-kill will decrease a tumor cell population by one order of magnitude)
What is a myelosuppresssant?
Drug that suppresses the formation of mature blood cells such as erythrocytes, leukocytes, and platelets. This effect is also known as “bone marrow suppression”
What is an oncogene?
Mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells
What is rescue therapy?
Administration of endogenous metabolites to counteract the effects of anticancer drugs on normal (nonneoplastic cells)
What does the term vesicant mean?
Drug that causes blisters on contact with tissues. Such drugs can be particularly damaging to veins if administered in high concentrations into small vessels (e.g. alyklating agent mechlorethamine)
When are CCS drugs most active and effective?
usually most active in a specific phase of the cell cycle and are particularly effective when a large proportion of the tumor cells are proliferating (i.e. high growth fraction)
Cytotoxic drugs obey what order of kinetics?
FIRST ORDER
given dose kills a constant proportion of a cell population rather than a constant number of cells
What are the possible mechanisms of resistance to anticancer drugs?
INCREASED DNA REPAIR (alkylating agents and cisplatin)
FORMATION OF TRAPPING AGENTS (bleomycin, cisplatin, anthracyclines)
CHANGES IN TARGET ENZYME (methotrexate)
DECREASED ACTIVATION OF PRODRUG (purine and pyrimidine antimetabolites)
INACTIVATION OF ANTICANCER DRUGS (purine and pyrimidine antimetabolites)
DECREASED DRUG ACCUMULATION (multidrug resistance; increased expression of normal gene -MDR1 gene-for cell surface P-glycoprotein)
Name the Alkylating Agents
NITROGEN MUSTARDS (chlorambucil, cyclophosphamide, mechlorethamine)
NITROSOUREAS (carmustine, lomustine)
ALKYLSULFONATES (busulfan)
Cisplatin, Dacarbazine, Procarbazine
Discuss the basic MOA and mechsim for resistance to Alkylating Agents
CCNS drugs!!!
Form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base pairing, and DNA strand breakage
Tumor cell resistance to these drugs occurs through increased DNA repair, decreased drug permeability, and production of trapping agents such as thiols
Cyclophosphamide
M: covalently X-link (interstrand) DNA at guanine N-7. Require bioactivation by liver (CYP450 mediated transformation). one of the breakdown products is acrolein
U: solid tumors, leukemia, lymphomas, and some brain cancers
T: myelosuppresion, hemorrhagic cystitis resulting from formation of acrolein, partially prevented by mesna (thiol group of mesna binds toxic metabolite; prevents damage to bladder)
Mechlorethamine
U: Hodgkin’s lymphoma
T: GI distress, myelosuppresion, alopecia, and sterility are common. Marked vesicant actions!
Platinum Analogs (Cisplatin, Carboplatin, Oxalplatin)
M: Cross-link DNA
U: Testicular, bladder, ovary, and lung carcinomas. Oxaliplatin is used in advanced colon cancer.
T: nephrotoxicity and acoustic nerve damage. Renal toxicity can be reduced by use of mannitol with forced hydration.
PK: IV
Compare and contrast the 3 platinum analogs
Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but it has greater myelosuppressant actions.
Oxiplatin causes DOSE LIMITING neurotoxicity
Procarbazine
M: forms hydrogen peroxide, which generates free radicals that cause DNA strand scission
U: component of regimens for Hodgkin’s lymphoma
T: myelosupprassant and causes GI irritation, CNS dysfunction, peripheral neuropathy, and skin reactions. Inhibits enzymes including MAO and those involved in hepatic drug metabolism. Disulfiram-like rxns have occured with EtOH. Leukemogenic.
PK: orally active, penetrates CSF. hepatic elimination
Busulfan
M: alkylates DNA
U: CML. Also able to ablate patient’s bone marrow before marrow transplantation.
T: pulmonary fibrosis, hyperpigmentation
Nitrosoureas (carmustine and lomustine)
M: require activation. cross BBB –> CNS
U: brain tumors (including glioblastoma multiforme)
T: CNS toxicity (dizziness, ataxia)
Name the antimetabolite drugs
Antagonists of folic acid (methotrexate)
Purines (mercaptopurine, thioguanine)
Pyrimidines (fluorouracil, cytarabine, gemcitabine)
What phase of the cell cycle do the antimetabolite drugs act on?
CCS drugs acting primarily in the S phase of the cell cycle
What is the MOA of Methotrexate
substrate for and inhibitor of DHFR –> decrease in synthesis of thymidylate, purine nucleotides, and AA and thus inerferes with nucleic acid and protein metabolism.
formation of polyglutamine derivatives of methotrexate appears to be important for cytotoxic actions.
What is the clinical use and toxicity associated with Methotrexate?
U:
- Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas
- Non-neoplastic: abortion, ectopic pregnancy, RA, psoriasis
T: myelosuppresion, macrovesicular fatty change in liver, toxic effects on GI mucosa (mucositis), teratogenic
How is myelosuppresion reversible with Methotrexate?
toxic effects of methotrexate on normal cells may be reudced by administration of folinic acid (leucovorin); this strategy is called “leucovorin rescue”
What is the PK of Methotrexate?
oral and IV administration; can’t reach CNS
not metabolized and its clearance is dependent on renal function
What is the mechanism of resistance to Methotrexate?
decreased drug accumulation
changes in the drug sensitivity or activity of DHFR
decreased formation of polyglutamates
Mercaptopurine (6-MP) and Thioguanine (6-TG)
M: purine (thiol) analogs that decrease purine synthesis. activated by HGPRT
U: leukemias
T: bone marrow suppression is DOSE LIMITING, but hepatic dysfunction also occurs (cholestasis, jaundice, necrosis).
PK: low oral bioavailability becuase of first-pass metabolism by hepatic enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by allopurinol.
5-Fluorouracil (5-FU)
M: pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase –> decrease dTMP –> decrease DNA and protein synthesis
U: colon cancer, TOPICAL use for keratosis and basal cell carcinoma
T: myelosuppression, GI distress and alopecia
PK: IV; enters CSF. Elimination via metabolism
What is the mechanism of resistance to 5-FU
decreased activation of 5-FU
increased thymidylate synthase activity
reduced drug sensitivity of this enzyme
Cytarabine (ARA-C)
M: pyrimidine antimetabolite; activated by kinases to AraCTP, an inhibitor of DNA polymerases
U: leukemias, lymphomas
T: leukopenia, thrombocytopenia, megaloblastic anemia
Resistance can occur as a result of decreased uptake or it’s decreased conversion to AraCTP
Whats makes Cytarabine unique from the rest of the antimetabolites?
It is most specific for the S phase of the cell cycle
Gemcitabine
M: Deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form.
Diphosphate form inhibits ribonucleotide reductase and thereby diminish the pool of deoxyribonunucleoside triphosphates required for DNA synthesis.
Triphosphate form causes chain termination
U: initially approved for pancreatic cancer, now widely used.
T: neutropenia
Name the plant alkaloids
CCS drugs Vinca alkaloids = vinblastine, vincristine, vinorelbine Podophyllotoxins = etoposide, teniposide Camptothecins = topotecan, irinotecan Taxanes = paclitaxil, docetaxel
Vinblastine, Vincristine, Vinorelebine
M: block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules: “Microtubules are the VINes of your cells”
U: solid tumors, leukemias, lymphomas
T:
- Vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus
- VinBLAStine blasts bone marrow (suppression)
PK: must be given parenterally. no CSF penetration. cleared mainly by biliary excretion.
Etoposide and Teniposide
M: inhibit topoisomerase II –> increased DNA degradation. also inhibits mitochondrial electron transport. most active in late S and early G2 phases of the cell cycle
U: used in combo w drugs for lung (small cell), prostate and testicular
T: myelosuppression, GI irritation, alopecia
PK: oral administration; elimination via kidneys
Topotecan and Irinotecan
M: inhibit topoisomerase I. damage DNA by inhibiting an enzyme that cuts and releases single DNA strands during normal DNA repair process
U: Topotecan used as second-line therapy for advanced ovarian cancer and for small cel lung cancer. Irinotecan used for metastatic colorectal cancer
T: myelosuppression and diarrhea
Discuss the PK of Topotecan and Irinotecan?
Irinotecan is a prodrug that is converted in the liver into an active metabolite.
Topotecan is eliminated renally, whereas Irinotecan and its metabolite are eliminated in the bile and feces
Paclitaxel and Docetaxel
M: hyperstabilixze polymerized microtbules in M phase so that mitotic spindle cannot break down (anaphase cannot occur) - “It is TAXing to stay polymerized”
U: advanced breast and ovarian carcinoma
T: Paclitaxel causes neutropenia, thrombocytopenia, peripheral neuropathy, infusion reactions. Docetaxel causes neurotoxicity and BM depression
PK: IV
How do the taxanes differ from the vinca alkaloids in MOA?
Both interefere with mitotic spindle
Taxanes prevent microtubule DISASSEMBLY into tubulin monomers whereas Vinca Alkaloids prevent ASSEMBLY of tubulin dimers into microtubules
Name the ABXs
doxorubicin daunorubicin bleomycin dactinomycin mitomycin
Doxorubicin and Daunorubicin: MOA
Anthracyclines that intercalate between base pairs, inhibit topoisomerase II, and generate free radicals. they block the synthesis of RNA and DNA and cause DNA strand scission. Membrane disruption also occurs. These are CCNS drugs
Doxorubicin and Daunorubicin: PK and Use
PK: must be given IV. metabolized in the liver and products are excreted in bile and urine
Doxorubicin used in lymphoma, myelomas, sarcomas, and breast, endometrial, lung, ovarian and thyroid cancers
Daunorubicin: acute leukemias
What is the most distinctive adverse effect of Doxorubicin and Daunorubicin?
most distinctive adverse effect is cardiotoxicity, which includes initial electrocardiographic abnormalities (with the possibility of arrhytmias) and slowly developing cardiomyopathy and CHF
What can you administer with Doxorubicin and Daunorubicin to protect against the distinctive adverse effect?
Dexrazoxane is an inhibitor of iron-mediated free radical generation, may protect against cardiotoxicity. Liposomal formulations of doxorubicin may be less cardiotoxic
Bleomycin
M: generates free radicals, which bind to DNA, cause strand breaks, and inhibit DNA synthesis. CCS drug active in the G2 phase of tumor cell cycle
U: component of treatments for lymphoma, testicular cancer, and squamous cell carcinomas
T: pulmonary dysfunction (develops slowly and is DOSE LIMITING), hypersensitivity reactions, mucocutaneous reactions
What is Bleomycin inactivated by?
Must be given parenterally
Inactivated by tissue aminopeptidases, but some renal clearance of intact drug also occurs
Dactinomycin
M: CCNS drug that binds to dSDNA and inhibits DNA-dependent RNA synthesis.
U: melanoma and Wilm’s tumor
T: marrow suppression, skin reactions, GI irritation
PK: must be given parenterally and both intact drug and metabolites are excreted in bile
Mitomycin
M: CCNS drug that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA
U: hypoxic tumor cells
T: severe myelosuppresion and is toxic to heart, liver, lung, and kidney
PK: given IV and rapidly cleared via heptic metabolis
Common Chemotoxicities: CHEMO-TOX MAN
Cisplatin/Carboplatin: acoustic nerve damage (and nephrotoxicity) Vincristine: peripheral neuropathy Bleomycin, Busulfan: pulmonary fibrosis Doxorubicin: cardiotoxicity Trastuzumab: cardiotoxicity Cisplatin/Cardioplatin: nephrotoxic (and acoustic nerve damage) CYclophosphamide: hemorrhagic cystitis 5-FU: myelosuppresion 6-FU: myelosuppresion Methotrexate: myelosuppresion
What are the cardinal principles of combination chemotherapy?
Toxicity
Use drugs that work on different mechanisms
Resistance
What concurrent agent do you administer with MTX and 5-FU?
What are the consequences?
Administer: Leucovorin
Consequence: metabolic rescue with MTX and enhanced action with 5-FU
IV dosing to prevent hyperuricemia
Prevent high levels of uric acid in the renal tubules, because it precipitates out and cause renal failure.
A patient with lung cancer recieves a course of chemotherapy before surgery. Drug use in this context is called…
Neo-adjunctive therapy - “neo” means before, giving the treatment to shrink the tumor
What is sensitizing therapy
look up
What is adjunctive therapy
comes after the surgery
Analysis of a biopsy from a solid tumor indicates rate high levels of glutathione. The activity of which drug would most likely be diminished?
Cisplatin
Bleomycin
Doxorubicin and Daunorubicin
