5-Fluorouracil resistance

Parisot D, MC Malet-Martino, P Crasnier, R Martino (1989) nuclear magnetic resonance analysis of 5-fluorouracil metabolism in wild-type and 5-fluorouracil-resistant Nectria haematococca. Appl Environ Microbiol 55 2474-2479. 

E. Bloemena, S. Meljer, G. Jansen, C.J. van Groeningen, H.M. Pinedo, Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism, Biochem. Biophys. Acta (Molecular Basis of Disease) 1587 (2002) 194-205. 

Shin YK, Yoo BC, Chang HJ, Jeon E, Hong SH, Jung MS, et al. Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res 2005 65(8) 3162-3170. 

Miller JE, Vlasakova K, Glaab WE, Skopek TR. A low volume, high-throughput forward mutation assay in Salmonella typhimurium based on fluorouracil resistance. Mutat Res 2005 578 210-24. 

The active principle of both TAS-102 and FTC-092 with anti-cancer effect is Trifluridine (7). As in the case of Fluorouracil, one of the mechanisms by which compound 7 exhibits its antitumor activity is inhibition of thymidylate synthase [100], More precisely, Trifluridine is transformed into a,a,a-trifluorothymidine monophosphate (76) by thymidine kinase (Scheme 21) similarly to the Fluorouracil derivatives discussed in the previous sections, compound 76 is true inhibitor of thymidylate synthase. However, compound 7 exhibits an anticaneer effect on colorectal cancer cells that have acquired Fluorouracil resistance as a result of the overexpression of thymidylate synthase. 

In vitro nifedipine inhibits proliferation of colon cancer cells with a DNA mismatch repair defect that are resistant to 5-fluorouracil. Whether this also... 

Johnston PG, Drake JC, Trepel J et al. Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res 1992 52 4306-4312. 

Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S et al. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 1997 15 3223-3229. 

THC is effective in several chemotherapy regimens, including methotrexate and the doxorubicin/cyclophosphamide/fluorouracil combination. Cisplatin treatment, however, is more resistant. Side effects of THC are generally well tolerated, and use may be limited in the elderly or with higher doses. Nabilone is a synthetic cannabinoid that is more effective than prochlorperazine in chemotherapy-induced emesis, including cisplatin. Its side effects are similar to THC. Levonantradol is another synthetic cannabinoid with antiemetic effects, and may be administered orally or intramuscularly. The side effect of dysphoria may limit its use. 

Dolnick BJ, Pink JJ. Effects of 5-fluorouracil in dihydrofolate reductase and dihydrofolate reductase mRNA from methotrexate-resistant KB cells. J Biol Chem 1985 260 3006-3014. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

Unfortunately, many human cancers have a large proportion of cells in the resting phase, and these cells are also resistant to the class 3 agents, which include cyclophosphamide, dactinomycin, and fluorouracil. 

A patient of yours has been receiving 5-fluorouracil as palliative therapy for adenocarcinoma of the pancreas. You suspect that the patient has become resistant to the treatment. You want to understand the most likely cause of the resistance before you select another agent. Which of the following is the most likely cause ... 

There is no evidence that 5-fluorouracil becomes unable to penetrate tumor cells. There may be an increase in P-glycoprotein, but this is not usually associated with 5-fluorouracil. There may be an induction in the drug metabolism for some antineoplastic drugs, but this does not appear to be the case for 5-fluorouracil. Increased metallothionein content has been associated with resistance in the case of cisplatin but not 5-fluorouracil. 

Several possible mechanisms of resistance to 5-fluo-rouracU have been identified, including increased synthesis of the target enzyme, altered affinity of thymidy-late synthetase for FdUMP, depletion of enzymes (especially uridine kinase) that activate 5-fluorouracil to nucleotides, an increase in the pool of the normal metabolite deoxyuridylic acid (dUMP), and an increase in the rate of catabolism of 5-fluorouracil. 

Wang TL, Diaz LA, Jr., Romans K et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl AcadSci USA 2004 101 3089-3094. 

Aschele C, Sobrero A, Faderan MA et al. Novel mechanism(s) of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 1992 52 1855-1864. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Two Phase III clinical studies of orally administered capecitabine in over 1,200 patients with untreated metastatic colorectal cancer demonstrated at least equal efficacy and improved tolerability versus the Mayo Clinic regimen of intravenous 5-fluorouracil/leucovorin administration. The overall response rate for patients taking capecitabine orally was 21%, versus 14% for the intravenous 5-FU/leucovorin regimen. A median 53-month follow-up revealed a three-year disease-free survival rate of 66% for capecitabine versus 63% for 5-FU/leucovorin patients. International Phase II trials also demonstrated therapeutic benefits of capecitabine monotherapy for women with metastatic breast cancer that was either resistant to both paclitaxel and anthracycline therapy. Orally administered at the twice-daily 1,250 mg/m2 regimen (cycles of two weeks of therapy followed by a week of rest), the tumor response rate was in the range of 20-25%. In addition, combination of capecitabine with a taxane yielded a unique survival benefit compared to the previous standard of taxane monotherapy for anthracycline-resistant breast cancer.13,14... 

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