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Colorectal Carcinoma

Pharmacology for colorectal carcinoma

QuestionAnswer
What classes of chemotherapeutic agents are available for colon cancer? 1. DNA-damaging agents 2. Anti-metabolites 3. Molecularly targeted drugs (cancer specific)
What DNA damaging agents are used to treat colon cancer? 1. Platinum compounds 2. Topoisomerase inhibitors
What is the formula for colon cancer chemotherapy? Antimetabolite + (Platinum compound OR Topo-I inhibitor) +/- Molecular-targeting agent
Which pyrimidine antimetabolite is often used for colon cancer? 5-flourouracil
In general, how do antimetabolite drugs work? They inhibit chemicals that are part of normal metabolism, thus leading to toxic effects on cells, such as halting cell growth and division.
What is the MOA of 5-FU? It inhibits thymidylate synthase (FdUMP); interferes with RNA synthesis (FUTP); and has some effects on DNA synthesis (FdUTP).
This drug, which is used in combination with methotrexate, is also used in combination with 5-FU. Leucovorin
An orally stable prodrug that is enzymatically converted to 5-FU within tumors? Capecitabine (Xeloda)
Pros and cons of using Capecitabine over 5-FU Pro: Orally active (no need for continuous I.V. infusions) Con: Costs $3600/month (vs $100/month)
Deficiency of this enzyme will increase the risk for 5-FU toxicity in 5-FU users, due to inability to metabolize 5-FU. Dihydropyrimidine Dehydrogenase (DPD)
Fully reduced folate that potentiates cell killing by 5-FU. Leucovorin (Folinic acid)
How do colorectal tumors become resistant to 5-FU? They overexpress thymidylate synthase (TS) or mutate it to a resistant form.
Platinum compounds Cisplatin, Carboplatin, Oxaliplatin
MOA of Oxaliplatin 1. Intra-chain cross-linking of DNA (N7 and 06 of guanine are susceptible) 2. Generation of free radicals 3. Inhibits dTTP synthesis (needed for synthesis of DNA) by blocking TS
Toxicities of Oxaliplatin Hearing loss; Bone marrow toxicity; Mutagenic; Peripheral neuropathy
MOA of Irinotecan (aka CPT-11 and Camptosar) Inhibits topoisomerase I
Topoisomerases Enzymes that unwind DNA, in order for DNA to control the synthesis of proteins, and to facilitate DNA replication.
Ironotecan is a synthetic analog of this natural product Camptothecin
Side effects of Irinotecan Severe diarrhea and immunosuppression due to neutropenia
Patients with this enzyme deficiency display greater toxicity with Irinotecan UGT1A1 enzyme
What is CAPOX? Colon cancer regime of Capecitabine plus Oxaliplatin
What is FOLFOX? Colon cancer regime of Oxaliplatin, Leucovorin, and 5-FU
Monoclonal antibodies against epidermal growth factor receptor (EGFR) that cause T-cell mediated killing and receptor blockade Cetuximab (Erbitux) and Panitumumab
Monoclonal antibodies against vascular endothelial growth factor (VEGF); blocks angiogenesis Bevicizumab/Avastin
Blockade of the EGFR receptor blocks binding of this hormone Growth factor; results in inhibition of cell growth and leads to cell death
Over-expession of this receptor is found in many human cancers (~75%) including those of the colon and rectum EGFR
Is indicated for treatment of Stage IV (metastatic) colorectal cancer after failure of Irinotecan Erbitux/Cetuximab
Side effects of Erbitux/Cetuximab Rash, infusion reaction, darrhea, and rare lung toxicity
Avastin/Bevacizumab is approved for what 3 leading causes of cancer death 1. Metastatic colorectal cancer 2. Advanced non-squamous, non-small cell lung cancer 3. Metastatic HER2-negative breast cancer
Side effects of Avastin/Bevacizumab G.I. perforation; wound healing complications; hemorrhage; non-GI fistula formation; arterial thromboembolic events; neutropenia and infection; nephrotic syndrome, CHF; hypertension; proteinuria; headache
Created by: MarcoB78
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