Oxaliplatin resistance

Stordal B, Peters G, Davey R. Similar ehromosomal changes in cisplatin- and oxaliplatin-resistant sublines of the H69 SCLC eell line are not associated with platinum resistance. Genes Chromosomes Cancer 2006 45 1094-1105. 

Notes See the footnote of Table 3. bHuman ovarian carcinoma. cDoxorubidn-resistant ovarian carcinoma. Oxaliplatin-resistant ovarian carcinoma. Cisplatin-resistant ovarian carcinoma. 

Samimi, G. Manorek, G. Castel, R. Breaux, J.K. Cheng, T.C. Berry, C.C. Los, G. Howell, S.B. cDNA microarray-based identification of genes and pathways associated with oxaliplatin resistance. Cancer Chemother. Pharmacol. 2005, 55, 1-11. 

Oxaliplatin belongs to the group of diaminocyclohex-ane platinum complexes that can overcome platinum resistance. Its place in the primary and adjuvant treatment of colon cancets is being defined. It is prominently neurotoxic. 

O. Rixe, W. Ortuzar, M. Alvarez, R. Parker, E. Reed, K. Pauli, T. Fojo, Oxaliplatin, Tet-raplatin, Cisplatin, and Carboplatin Spectrum of Activity in Drug-Resistant Cell Lines and in the Cell Lines of the NCI s Anticancer Drug Screen Panel , Biochem. Pharmacol. 1996, 52, 1855 - 1865. 

Cetuximab has modest activity in relapsed colorectal cancer as a single agent but is more effective with irinotecan and possibly oxaliplatin based regimens where a doubling of the response rate has been observed. There is some evidence that cetuximab may reverse irinotecan resistance. Toxic effects of cetuximab include hypersensitivity reactions, malaise, nausea, headache and an acneiform rash. 

Reconstitution of full-length BRCAl into mouse embryonic fibroblast cells with a disrupted BRCAl led to an increase in resistance to several DNA damaging agents, including the platinum compounds carboplatin and oxaliplatin, the topoisomerase 1 drugs irinotecan and topotecan, and the topoisomerase 11 drugs doxorubicin and etoposide (61). 

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. 

Oxaliplatin (5) (recently renamed Eloxatin) has been approved for the secondary treatment of metastatic colorectal cancers. It appears to have a different spectrum of activity compared to cisplatin, and has been shown to circumvent cisplatin resistance. The MMR protein complex binds to DNA globally modified by cisplatin, but not to that by oxaliplatin. Furthermore, MMR-deficient cells are shghtly more resistant to cisplatin, but not to oxahplatin. It has been proposed that steric effects caused by the 1,2-diaminocyclohexane ring may prevent the MMR complex from recognizing the lesion. 

Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M and Howell SB. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin. Cancer Res. 2004 10 4661-4669. 

Rixe O, Ortuzar W, Alvarez M et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute s Anticancer Drug Screen panel. Biochem Pharmacol 1996 52 1855-65. 

Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to flie same leucovorin and fluorouracil regimen. J Clin Oncol 1999 17 3560-3568. 

In this new class of platinum complexes some examples do not present the necessary cis configuration with respect to the chlorines. Oxaliplatin has been approved for clinical use in France and China for colorectal cancer. The interest in developing platinum complexes that bind to DNA in a fundamentally different manner to cisplatin is an attempt to overcome the resistance pathways that have evolved to eliminate the drug. 

Resistance to cisplatin, but not oxaliplatin, is partly mediated by loss of function in mismatch repair (MMR) proteins. By contrast, MMR repair proficiency is not required for oxaliplatin cytotoxicity. In the absence of effective repair of DNA-platinum adducts, sensitive cells cannot replicate or transcribe affected portions of the DNA strand. Some DNA polymerases can bypass adducts, possibly contributing to resistance. Overexpression of Cu efflux transporters ATP7A and ATP7B correlates with poor survival after cisplatin-based therapy for ovarian cancer. 

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