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What are the top 3 cancers in each sex?
- Men: prostate > lung > colon/rectum
- Women: breast > lung > colon/rectum
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Which anticancer Rx act as antimetabolites? [BOOM]
- Mercaptopurine,
- Methotrexate,
- Fluorouracil
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Which cause DNA damage? [BOOM]
- Busulfam,
- mechlorethamine,
- carmustine,
- cyclophosphamide,
- cisplatin
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DNA function? [BOOM]
Daunorubicin, doxorubicin, bleomycin, topoisomerase
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Transcription? [BOOM]
Dactinomycin
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Protein synthesis? [BOOM]
Aspariginase
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What anticancer Rxs alter protein fxn? [BOOM]
Vinblastine, vincristine, paclitaxel
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What normal cells are often most affected by cancer Tx?
Fast growing cells: marrow, GI, hair follicles, renal, hepatic, reproductive, teratogenic
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What is radiation recall?
Tx c chemo after radiation may cause appearance of radiation burns from previous radiation
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What rationale should be considered when combining chemo Tx?
Don't use multiple Rxs that cause marrow suppression because they will not Inc the therapeutic index
-
What are the alkylating agents?
Mechlorethamine, cyclophosphamide, busulfan, carmustin, streptozocin, cisplatin
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What is their MOA?
- Alkylate DNA --> cause miscoding, breakage, crosslinking
- NOT cell cycle specific (can be given as a bolus)
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What toxicities are common to the alkylating agents?
- Vesicants: tissue damage @ injection site (except cyclophosphamide)
- N/V/D
- Rapidly proliferating cells: marrow, GI, sperm, hair
- Immunosuppression
- Teratogenesis, sterility
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Why is cyclophosphamide not a vesicant?
It is a pro-Rx that must be activated in the liver
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What is the MOPP regimen and when is it used?
- Mechlorethamine, vincristine (Oncovin), prednisone, procarbazine
- Used in: Hodgkin's, lymphocytic leukemia, lymphosarcoma
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What is the unique toxicity of mechlorethamine?
Hyperuricemia --> acute renal failure, nephrolithiasis
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What is the Tx of hyperuricemia?
- Alkalinize urine and use allopurinol (xanthine oxidase inhibitor)
- Reminder: may provoke gouty attack in gout, use colchicine prophylaxis
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What activates cyclophosphamide?
P450
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What are its uses?
Wide use: leukemia, solid tumors, immunosuppression in transplants
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What are its side effects?
- Hematologic toxicity (immune suppression)
- Hemorrhagic cystitis [BOOM] --> prevented c MESNA
- SIADH [BOOM]
-
What is interesting about the pharmacokinetics of chlorambucil?
Slow acting
-
When is chlorambucil used?
CLL, myeloma, autoimmune dz
-
What are the uses of thiotepa?
- Bladder CA
- 2nd choice in breast and ovarian CA
-
When is busulfan used?
- CML
- Reminder: Philadelphia chromosome t(9;22) BCR-ABL gene tyrosine kinase mutation, ONLY leukemia c thrombocytosis
- Also treated c imatinib (Gleevec)
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What is its unique toxicity?
Hyperuricemia --> treat c allopurinol
-
What nitrosoureas are lipophilic and cross BBB?
Carmustine, lomustine --> used for gliomas and other brain CA
-
What is the MOA of nitrosureas?
Inhibit DNA/RNA synthesis --> kill in ALL phases of cycle
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What are the uses of carmustine?
Hodgkin's and non-Hodgkin's lymphoma, multiple myelomas, melanoma, GI, brain tumors
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What is its major toxicity?
Profound myelosuppression --> delayed
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When is lomustine used?
Brain tumors, melanoma, GI (all side effects same as carmustine)
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What additional unique toxicity is seen c lomustine and carmustine? [BOOM]
Pulmonary toxicity, renal toxicity
-
What is unique about streptozocin? [BOOM]
Selective for Beta-islet cells in pancreas
-
How does cisplatin differ from the other alkylating agents in structure?
It is a platinating agent --> crosslinks DNA
-
How does cisplatin interact c other anticancer agents?
- Sensitizes the cells to radiation
- Does NOT cause myelosuppression --> combine c Rx that cause myelosuppression to Inc. effectiveness
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What is its spectrum?
Broad: testicular, ovarian, bladder, head, neck, lung
-
What are its toxicities?
- Acoustic nerve damage, anaphylaxis, renal toxicity
- Reminder: aminoglycosides also cause ototoxicity
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What are the antimetabolite Rxs?
Methotrexate, mercaptopurine, fluorouracil, cytarabine, hydroxyurea
-
What is the methotrexate MOA?
- Inhibits DHF reductase to prevent DHF ? THF
- This prevents formation of thymidylate which blocks DNA, RNA, & protein synthesis
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What is the consequence of inhibition of DHF reductase?
Myelosuppression
-
What is used to ? toxicity of methotrexate?
Leucovorin (THF)
-
What are the uses of methotrexate?
- ALL, Burkitt's, Non-Hodgkin's lymphomas
- Reminder:
Burkitt's is t(8;14) d/t EBV, *starry sky* appearance of B-cells- Reminder
: ALL most common CA in children, B-cell > T-cell
- Choricoarcinoma
- Breast, head, neck, ovary, and bladder carcinomas
- Osteosarcoma
- Immunosuppression: RA, psoriasis
-
What is methotrexates unique toxicity?
Hepatotoxicity
-
What are the purine antimetabolites?
Mercaptopurine, thiguanine
-
What is their MOA?
- Converted to nucleotide by HGPRT --> inhibit DNA and RNA synthesis
- Not cell cycle specific
- Resistance is via dec. in HGPRT
- Reminder: HGPRT in purine salvage pathway, defective in Lesch-Nyhan (XR) --> accumulation of uric acid
-
What is the major Rx interaction of mercaptopurine? [BOOM]
Metabolized by xanthine oxidase --> allopurinol Inc. effectiveness and toxicity
-
When is it used?
Leukemias
-
What are its toxicities?
- Bone marrow suppression
- Jaundice d/t cholestasis
-
What are the pyrimidine antimetabolites?
5-fluorouracil and cytarabine
-
What is the the 5-FU MOA?
Inhibits thymidylate synthase (rate limiting enzyme in DNA synthesis)
-
Where does it act in the cell cycle?
G1 and S phases
-
How does it react c leucovorin?
Needs THF to form thymidylate synthase complex, so leucovorin Inc. its effectiveness
Leucovorin has opposite effect on methotrexate
-
What are the uses of 5-FU?
- Broad spectrum use in solid tumors
- Topical for basal cell carcinoma
-
What is the cytarabine MOA?
Competes c dCTP --> chain termination in DNA synthesis
-
In what phase of the cell cycle does cytarabine work?
S phase
-
When is it the DOC?
AML (Reminder: t(15;17) in promyelocytic leukemia, Auer rods)
-
What is the MOA of daunorubucin and doxorubicin?
Intercalate and bind DNA in S-phase, generate free radicals
-
What are their toxicities?
- Cardiotoxicity--> 2ndary to production of free when combined c Fe
- Based on peak concentration --> infuse Rx slowly
- Treat c iron chelator (dexrazoxane), worse when combined c Herceptin
- Turn urine red
- Vesicant, depresses marrow, alopecia
-
When is daunorubicin used?
Leukemias (doxorubicin has a wide use)
-
What is the bleomycin MOA?
- Directly damages (*chops up*) DNA
- Cell cycle specific (G2 and M)
-
How is it given?
Orally or into bladder
-
When is it used?
Highly effective for testicular and ovarian CA, used in many others
-
What is its major toxicity?
Pulmonary fibrosis
-
What is the dactinomycin MOA?
Binds DNA between C-G, causes strand breaks, stops RNA synthesis
-
What are its uses?
- Wilm's tumor, rhabdomyosarcoma, choriocarcinoma, sarcomas
- Immune suppression --> transplants
-
What is the major toxicity of dactinomycin?
Radiation recall
-
What are the plant alkaloids?
Vincristine, vinblastine, paclitaxel (Taxol)
-
What is their MOA?
Vincristine, vinblastine --> destabilize microtubules
Paclitaxel --> stabilizes microtubules
-
When is vincristine used?
Leukemia, Hodgkin's, NHL
-
What are the vincristine toxicities?
- Neurotoxicity--> "velvet glove" tingling in the hands [vincristine, crisps the nerves]
- Low myelosuppression (used in many combo therapies)
-
What are the vinblastine toxicities?
Myelosuppression [vinblastine, blasts the blood], less neurotoxic
-
When is vinblastine used?
Testicular carcinoma, Hodgkin's, Kaposi's sarcoma
-
When is paclitaxel used?
Advanced breast, ovary, lung, head, neck
-
What are its toxicities?
Peripheral neuropathies, myalgia, arthralgia, hypersensitivity, myelosuppression
-
What is the MOA of etoposide?
Binds topoisomerase II --> DNA strand breaks
-
When is it used?
Testicular CA, myelosuppression
-
What is the MOA of topotecan?
Binds topoisomerase I --> cell cycle arrest, DNA damage
-
When is it used?
Ovarian CA, myelosuppression
-
What is the MOA of asparaginase? [BOOM]
Cancer cells require asparagine, but many lack asparagine synthase so they need exogenous forms. This Rx hydrolyzes asparagine --> aspartate
-
When is it used?
In combo for Tx of ALL
-
What is the MOA of interferon alfa-2a (Roferon)?
Dec. tumor cell proliferation
-
When is it used?
Hairy cell leukemia, Kaposi's sarcoma, condylomata acuminata
-
What are the toxicities?
- Flu-like Sx: myalgia, arthralgia
- CNS: depression
-
What is the MOA of IL-2?
Inc. T cell (CD8) to tumor cells
-
When is IL-2 used?
Advanced malignant melanoma, renal cell CA
-
What are the toxicities?
- Hypotension, edema, vascular leak, resp. insufficiency
- Anemia, thrombocytopenia
- N/V/D
-
What is the use of G-CSF?
Prevent or reverse neutropenia d/t antineoplastics
-
How are corticosteroids used in cancer Tx?
In cancers of the immune system, to combat radiation-induced edema
-
When are androgens used?
Breast CA
-
When are progestins used?
Endometrial/breast CA
-
What is the use of flutamide?
Blocks androgen receptors --> used in prostate CA
-
When are estrogens used?
Prostate CA
-
When are GnRH agonists used?
To shut down androgen production (block initial surge c flutamide)
-
What is the MOA of tamoxifen?
Estrogen antagonist in breast, agonist in uterus
-
What are the toxicities?
Hot flashes, nausea, uterine changes, Dec. HDL
-
When is trastuzumabe used?
HER2 antibody in HER2 expressing CA
-
What is its major toxicity?
Cardiotoxic
-
What is the imatinib (Gleevec) MOA?
Inhibitor of Bcr-Abl fusion tyrosine kinase (CML)
-
What is the major toxicity?
High rate of CHF
-
Which Rxs caue radiation recall?
Dactinomycin, hydroxyurea
-
Pulmonary fibrosis?
Bleomycin, busulfan
-
Neuropathy?
Vincristine, vinblastine, paclitaxel
-
Hyperuricemia?
Mercaptopurine, busulfan
-
Renal and acoustic nerve?
Cisplatin
-
Which Rx causes red urine?
Daunorubicin
-
Hepatotoxicity?
Mercaptopurine, BCNU, CCNU, methotrexate
-
Cystitis?
Cyclophosphamide
-
Cardiomyopathy?
Doxorubicin, daunorubicin, imatinib
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