Impact of the oxaliplatin-5 fluorouracil-folinic acid combination on respective intracellular determinants of drug activity

Fischel, Jean‐Louis; Formento, Patricia; Ciccolini, Joseph; Rostagno, Philippe; Etienne, Marie‐Christine; Catalin, J; Milano, Gérard

doi:10.1038/sj....bjc.6600185...

Cited by 8 publications

(10 citation statements)

References 18 publications

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“…Experiments looking at the mechanism of synergism between oxaliplatin and 5-fluorouracil (5fu) have uncovered a direct inhibitory effect of oxaliplatin on thymidylate synthase, preventing the incorporation of thymidine in nucleic acid synthesis 9 . This antimetabolite-like effect results in arrest of the mitotic process.…”

Section: Arrest Of Dna Synthesismentioning

confidence: 99%

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Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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Section: Arrest Of Dna Synthesismentioning

confidence: 99%

“…The exact mechanism of synergism between 5fu and oxaliplatin is complex, but experimental observations suggest that oxaliplatin can downregulate or inhibit dihydropyrimidine dehydrogenase, slowing the catabolism of 5fu 9 .…”

Section: Mechanism Of Action In Oxaliplatin-based Combinationsmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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“…[50][51][52][53][54] The efficacy of oxaliplatin plus LF (Oxali-FUFA) as first line of chemotherapy has been largely demonstrated in the last years in a large number of different clinical trials performed in patients with metastatic colo-rectal carcinoma. 51,55 More recently, it has been shown that Oxali-FUFA (following the FOLFOX 4 schedule proposed by De Gramon) is better tolerated, and leads to a higher objective response rate, a longer time to progression, and a longer overall survival than the IRI, LF, and 5-FU combination (ILF) proposed by Salts et al in patients with advanced colorectal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased raf-1 ubiquitin-dependent degradation

Caraglia

Marra

Budillon

et al. 2005

Cancer Biology & Therapy

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The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 µM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex. ABBREVIATIONS

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“…The exact mechanism of synergism of combinational treatment of OXA and 5-FU is complex, but experimental observations suggest that OXA can downregulate or inhibit dihydropyrimidine dehydrogenase, slowing the catabolism of 5-FU. [57][58][59] In our study, the in vitro cytotoxic effect of combining OXA (39 µM) and 5-FU (120 µM) was 1.65 and 1.44 times higher than that of the same amounts of OXA and 5-FU alone, respectively. Moreover, the cytotoxicity of a combination of free OXA (39 µM) and 5-FU (120 µM) was 1.80 times enhanced by treatment with a nanoemulsive form containing OXA/DCK (39 µM) and 5-FU (120 µM).…”

mentioning

confidence: 49%