Flashcards in Cancer Drugs Deck (128):
List the subclasses of alkylating agents.
(Below drugs are partly aklylators)
Platinum Drugs (cisplatin)
Dacarbazine (a triazene)
Procarbazine (a hydrazine)
List the Nitrogen Mustards. (and their common clinical uses)
Cyclophosphamide (non-Hodgkin's Lymphoma, breast/ovarian cancers, neuroblastoma)
Mechlorethamine (Hodgkin's lymphoma)
What is the MOA of Nitrogen Mustards?
Alkylate DNA at N7 guanine --> prevent DNA replication through abnormal base pairing, breakage through guanine excision, cross-linking
What are the mechanisms of resistance to Nitrogen Mustards ?
DNA repair, decreased drug permeability, and production of trapping agents such as thiols
LIst toxicities of Cyclophosphamide.
Expected: GI distress, myelosuppression, alopecia
Other: renal/urotoxic (hemorrhagic cystitis), cardiac dysfunciton, pulmonary toxicity, increased ADH secretion
List toxicities of Mechlorethamine.
GI distress, myelosuppression, alopecia, sterility
*also it is a VESICANT (causes blistering)
What drug is taken with Mesna? Why?
Cyclophosphamide to protect against acrolein (breakdown product during hepatic CYP450 mediated biotransformation of drug)
What is the consequence of acrolein?
causes renal (tubular acidosis, proximal damage, malreabsorption) and urotoxicity/bladder tumors (hemorrhagic cystits*)
What are the methods of resistance to cyclophosphamide?
DNA repair enzyme upregulation
What type of cells are affected by nitrogen mustard?
affects replicating cells (late G1-S)
List the alkyl sulfonates. What is its major us?
Busulfan (in chronic myelogenous leukemia)
What are the adverse effects of busulfan?
adrenal insufficiency, lung fibrosis, skin pigmentation
What is the ROA of nitrogen mustards?
oral, if available
What is the MOA of Busulfan?
Alkylate DNA, prevent DNA replication
What is the ROA of busulfan? How does it act in aqueous solution?
oral or IV
Spontaneous hydrolysis in aqueous solution --> liberates active methane sulfates
List examples of Nitrosoureas.
What is the MOA of Carmustine (BCNU)?
Alkylate DNA, prevent replication/ decomposition products carbomolyate proteins: inhibit DNA repair
True or false Nitrosoureas can access BBB.
True- lipophilic, nonionized--> crosses BBB (so useful for brain tumors)
List the platinum drugs? What are their common uses?
cisplatin (testicular carcinoma or cancer of bladder, lung, and ovary)
carboplatin (same as cisplatin)
oxaliplatin (advanced colon cancer)
What is the MOA of Lomustine (CCNU)?
Alkylate DNA, producing intra- or inter-strand crosslinks that prevent DNA replication
What are the toxicities located with cisplatin?
GI distress, mild hematoxicity, nephrotoxic and neurotoxic (peripheral neutopathy and acoustic nerve damage)
What are the toxicities located with carboplatin?
Less renal toxicity and less peripheral neuropathy and tinnitius than Cisplatin, thrombocytopenia (greater myelosuppressant actions)
What are the toxicities located with oxaliplatin?
dose limiting neurotoxicity
What is the system of elimination with platinum drugs?
What toxicities are associated with Carmustine (BCNU)?
Hepatic "veno-occlusive disease", CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia
What toxicities are associated with Lomustine (CCNU)?
CNS (seizures, dementia), pulm fibrosis, endocrine dysfunc, thrombocytopenia, leukopenia
What system metabolizes Nitrosoureas? What is its ROA?
What is the toxicity associated with dacarbazine?
Alopecia, skin rash, GI distress, myelosuppression, phototoxicity, and flulike syndrome
What is the MOA of procarbazine?
Reactive agent that forms hydrogen peroxide, which generates free radicals and causes DNA strand scission
What are the toxicities associated with procarbazine?
Disulfiram-like effect, leukopenia, GI irritation, CNS dysfunction, peripheral neuropathy, skin reactions
Inhibits MAO (and other enzymes
What is the common use of procarbazine?
What method of elimination is used for procarbazine?
What is the MOA of platinum drugs?
Alkylated DNA at N7 guanine after activation in water. Produced intrastrand G-A cross-links. Interrupts replication and transcription.
What are methods of resistance to cisplatin?
glutathione (traps alkylating agents)
What platinum drug is associated with development of AML (4yr after treament)?
What platinum drug is associated with break and miscoding--> p53 activation and induction of apoptosis?
True or false carboplatin and oxaliplatin are taken ONLY orally.
FALSE: taken ONLY IV
What is the MOA of dacarbazine?
Metabolically activated DNA methylating agent (on O6 guanine)
What are mechanisms of resistance to dacarbazine?
Removal of methyl groups from O6-guanine by AGT
True or false: procarbazine can penetrate CSF.
TRUE!! orally active and can penetrate most tissues
True or false: alkylating agents are CCNS drugs.
Antimetabolites are antagonists of what compounds?
Name a folic acid antimetabolite.
Name the purine antimetabolites.
Name a pyramidine antimetabolites.
fluorouracil, cytarabine, gemcitabine
True or false: antimetabolites are CCNS drugs.
FALSE: they are CCS drugs acting primarily in the S phase of the cell cycle
Other than cytotoxic effects on neoplastic cells, what is another function of antimetabolites?
What is the MOA of methotrexate. What compound is formed that is important for its action?
inhibits dihydrofolate reductase leading to decrease in synthesis of thymidylate, purine nucleotides, and amino acids (interferes with nucleic acid and protein metabolism)
*forms polyglutamate derivatives
What are the mechanisms of resistance to methotrexate?
-decreased drug accumulation
-changes in drug sensitivity/activity of dihydrofolate reductase
-decreased formation of polyglutamates
What is the ROA of methotrexate?
oral or IV
Methotrexate is poorly distributed to what tissue?
True or false: methotrexate is metabolized by the liver.
FALSE: methotrexate is NOT metabolized and it is cleared by RENAL function
When taking methotrexate, what is important to do?
stay well hydrated, in order to prevent crystallization of renal tubules
Methotrexate is used for what cancers?
choriocarcinoma, acute leukemias, etc.
Methotrexate has what uses outside of cancer?
Rhematoid arthritis psoriasis
Abortifacient in ectopic pregnancy
What are the toxicities associated with methotrexate?
Common: bone marrow suppression, toxic to skin and GI mucosa
Long-term: hepatotoxicity and pulmonary infiltrates/fibrosis
What is "leucovorin rescue"?
administration of folinic acid in order to reduce the toxic effects of methotrexate on normal cells
What is the MOA of purine antimetabolites (mercaptopurine and thioguanine)?
Activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism
What are methods or resistance to purine antimetabolites?
decrease activity of HGPRTase (activation)
increase activity of alkaline phosphatases (inactivation)
What is the DDI with allopurinol and mercaptopurine?
6-MP is metabolically converted in 1 of 3 ways, 1 of which is to thiouric acid (Allopurinol blocks this pathway and can cause drug toxicity)
What are the main uses for purine antimetabolites?
acute leukemias and chronic myelocytic leukemia
What are the toxicities associated with purine antimetabolites?
-bone marrow suppression (dose limiting)
-hepatic dysfunction (cholestasis, jaundice, necrosis)
What is the MOA of 5-fluorouracil?
Inhibition of Thymidylate Synthase, DNA synthesis inhibition via "thymineless death," gets incorporated into DNA -> inhibition of synthesis & function, interferes w/ mRNA translation
What are resistance mechanisms against 5-fluorouracil?
decreased activation of 5-FU
Increased thymidylate synthase activity
reduced drug sensitivity to this enzyme
What is the ROA of fluorouracil?
IV- widely distributed, even to CSF
topically- for some keratoses/superficial basal cell carcinomas
How is fluorouracil eliminated?
mainly by metabolism
What are the uses of fluorouracil?
bladder, breast, colon, head/neck, liver, and ovarian cancers
(also topical use)
What pyramidine antimetabolite is MOST specific for the S phase of the cell cycle?
What is the MOA of cytarabine?
Converted to ARA-CTP, which inhibits DNA polymerase-alpha
What are the resistance mechanisms against cytarabine?
decreased conversion to ARA-CTP
What is the MOA of gemcitabine?
converted to active diphosphate and triphosphate nucleotide forms that inhibits ribonucleotide reductase and diminished pool of DNTs required for DNA synthesis.
also can be incorporated into DNA and cause chain termination
What is the method of elimination of gemcitabine?
What is the clinical use of gemcitabine?
non-small cell lung cancer
What are the toxicities of gemcitabine?
True or false: plant alkaloids are CCNS drugs.
FALSE: CCS drugs that act in various specific phases of the cell cycle
List the subtypes of plant alkaloids.
What is the phase favored by Vinca Alkaloids?
LIst the vinca alkaloids.
What is the MOA of Vinca Alkaloids?
Bind to beta-tubulin: prevent microtubule polymerization (and mitotic spindle formation)
What are mechanisms of resistance against Vinca Alkaloids?
increased efflux of drugs via membrane drug transporters
What is the ROA of vinca alkaloids?
parenterally (can penetrate most tissues but CSF)
What is the elimination mechanism of vinca alkaloids?
What are the toxicities of vinca alkaloids?
vinblastine/vinorelbine: GI distress, alopecia, bone marrow suppression
vincristine: NO myelosuppression but DOES cause neurotoxic actions (areflexia, peripher neuropathy, paralytic ileus)
What is the phase favored by Podophyllotoxins?
late S to early G2 phases of cell cycle
LIst the Podophyllotoxins.
What is the MOA of Podophyllotoxins?
-Form complex w/ topoisomerase II & DNA to disrupt repair of dsDNA breaks
-Inhibits mitochondrial electron transport
What is the ROA of Podophyllotoxins?
What is the mechanism of elimination of Podophyllotoxins?
What are the toxicities associated with Podophyllotoxins?
Bone marrow suppression
List the camptothecins.
What is the MOA of camptothecins?
Inhibit DNA topoisomerase I and damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair process
Which camptothecin is a prodrug that is converted to active metabolite in liver?
True or false: all camptothecins are eliminated through the renal system.
False- topotecan is eliminated renally and irinotecan is eliminated in bile and feces
What toxicities are associated with camptothecin?
myelosuppression and diarrhea
List the taxanes.
What is the MOA of taxanes?
interfere with mitotic spindle and prevent microtubule DISASSEMBLY into tubulin monomers (different than alkaloids)
What is the ROA of taxanes?
What are the most common uses of taxanes?
advanced breast and ovarian cancers
What are the toxicities associated with paclitaxel?
possible hypersensitivity reaction during infusion
What are the toxicities associated with docetaxel?
bone marrow depression
List the antibiotics used in cancer treatment.
True or false: Doxorubicin and Daunorubucin are CCNS drugs?
What is the MOA of Doxorubicin and Daunorubucin?
intercalate between base pairs, inhibit topoisomerase II, and generate free radicals.
Block RNA/DNA synthesis, cause DNA strand scission, membrane disruption
What is the ROA and excretion mechanism of Doxorubicin and Daunorubucin?
Elimination: liver metabolism and excreted in bile and urine
What are the toxicities associated with Doxorubicin and Daunorubucin?
CARDIOTOXICITY (possibility of arrhythmias, cardiomyopathy, CHF)
bone marrow suppression
What may help to alleviate the cardiotoxicity of Doxorubicin and Daunorubucin?
dexrazoxane (inhibitor of free-radical administration)
True or False: Bleomycin is a CCNS drug?
FALSE: it is a CCS drug active in G2 phase of cell cycle
What is the MOA of Bleomycin?
Glycopeptides that generate free radicals which bind to DNA and cause strand breaks--inhibiting DNA synthesis
What is the ROA and excretion mechanism of Bleomycin?
Clearance: renal clearance
What are the toxicities associated with bleomycin?
Pulmonary dysfunction (pneumonitis, fibrosis)
Hypersensitivity (chills, fever, anaphylaxis)
Mucocutaneous reactions (blisters, alopecia, hyperkeratosis)
True or false: Dactinomycin is a CCNS drug.
What is the MOA of Dactinomycin?
binds to dsDNA and inhibits DNA-dependent RNA synthesis
What is the ROA and excretion mechanism of Dactinomycin?
Elimination of both intact and metabolites through bile
What are the toxicities associated with Dactinomycin?
bone marrow suppression
True or false: Mitomycin is a CCNS drug.
What is the MOA of Mitomycin?
metabolized by liver enzymes to form alkylating agent that cross-links DNA
What is the ROA and excretion mechanism of mitomycin?
Excretion: hepatic metabolism
What are the toxicities associated with mitomycin?
Toxic to heart, liver, lung, kidney
True or false: anticancer drugs obey 0 order kinetics.
FALSE: they obey the log kill hypothesis (1st order kinetics)
What are the 4 cardinal principles of combination chemotherapy?
2) Different MOAs
3) No/Minimal cross-resistance
4) Different pattern of toxicity
What two classes would you NEVER take together due to additive neurotoxicity?
vinca alkyloids and taxanes
cause "stocking glove syndrome"
What cancer drug has adverse effects on the kidney?
What can be taken BEFORE fluorouracil to make 5-FU more affective?
Leucovorin will get cells to start dividing rapidly, so more cells will be in the synthesis phase (where fluorouracil works!)
What can be taken with mercaptopurine to increase the toxicity of it?
What should be taken with cisplatin for cytoprotection?
What drugs can be administered to protect against tumor lysis syndrome?
Allopurinol (blocks xanthine oxidase at two steps)
Rasburicase (stimulates urate oxidase to change uric acid into allantoin
What is tumor lysis syndrome?
if too many tumor cells lyse at the same time, lots of cellular contents are put into the blood and are shunted to the kidney to be excreted (VERY nephrotoxic)