Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

Abstract

Summary A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC 50 ) of the double association without that drug divided by the IC 50 of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.

Biweekly oxaliplatin plus irinotecan and folinic acid-modulated 5-fluorouracil: a phase II study in pretreated patients with metastatic colorectal cancer

“…Moreover, our regimen was very active despite this dose reduction. This finding confirms the in-vitro observation, which highlighted the greatest contribution of OXA to the overall cytotoxicity of the triplet combination [19], and suggests that a slight dose reduction of this regimen in further clinical evaluation could not jeopardize its activity.…”

“…Moreover, an in-vitro study on two human colon cancer cell lines (SW620 and WIDR) reported the interaction of different simultaneous exposures to OXA, SN38 and 5FU modulated by FA (FUFA) [19]. In this study, the OXA + FUFA combination was always synergistic, the OXA + SN38 combination was either additive (when SN38 was applied after OXA) or antagonistic (when SN38 was applied first), SN38 + FUFA was always antagonistic, while the triple exposure (OXA+SN38+FUFA) was additive.…”

An Alternating Regimen of Irinotecan/ 5-Fluorouracil/Folinic Acid and Oxaliplatin/ 5-Fluorouracil/Folinic Acid in Metastatic Colorectal Cancer: A Phase II Trial

“…Preclinical studies showed a synergistic activity of the SN-38/L-OHP combination [14] and indicated that the sequence of administration is important. Further in vitro studies investigating combinations of 5-FU, CPT-11, and L-OHP have shown that a synergism occurs only when CPT-11 precedes 5-FU/L-OHP exposure [15].…”

Efficacy of Treatment with Irinotecan and Oxaliplatin Combination in FU-Resistant Metastatic Colorectal Cancer Patients

“…First, it would be interesting to see if a sequential regimen with FU/leucovorin followed by a combination of irinotecan and oxaliplatin is comparable to concomitant administration of all three drugs [22, 23, 24, 25]. The second question is that the combination tested is extremely interesting for patients that more likely will fail to fluoropyrimidine therapy, according to intratumoral levels of the specific enzymes within the drug’s anabolic and catabolic pathways.…”