Mechanisms of collateral sensitivity to fluorouracil of a cis-diamminedichloroplatinum(II)-resistant human non-small lung cancer cell line

Abstract

A cisplatin(CDDP)-resistant subline of a human lung cancer cell line, PC-7/CDDP, was 4.7-fold more resistant to CDDP than the parent line in a colony-forming assay. The sensitivity of this cell line to anthracyclines, vinca-alkaloid, etoposide, mitomycin C, and bleomycin was similar to that of the parental line, PC-7. However, PC-7/CDDP exhibited 4-fold higher sensitivity to fluorouracil (FUra). Possible mechanisms associated with the collateral sensitivity to FUra were studied in PC-7/CDDP cells. The sensitivity of both cell lines to FUra did not correlate with the effect of FUra on RNA. On the other hand, FUra induced a greater reduction in dTTP pools and more single strand breaks in PC-7/CDDP than in PC-7 cells. These results suggest that the pathway for de novo deoxyribonucleotide synthesis may be a target for FUra in PC-7/CDDP cells. However, inhibition of thymidylate synthase after FUra treatment did not correlate with the DNA-directed activity of FUra. Based on the above findings, the decreased salvage synthesis of dTTP was considered a possible mechanism of the greater reduction of dTTP pools in PC-7/CDDP cells. However, the activity of dThd kinase was the same in both cell lines. In the presence of physiological concentrations of exogenous dThd in the serum, uptake of dThd was less in PC-7/CDDP cells than that in PC-7 cells. Our data suggest that FUra-induced cytotoxicity in PC-7/CDDP cells is associated with the inhibition of dTTP synthesis and that the decreased uptake of dThd is a possible mechanism of the collateral sensitivity to FUra in PC-7/CDDP cells.

Experience of Oncopaz Cooperative Group with Oral Fluoropyrimidines in Tumors of the Stomach, Lung, Head and Neck, and Breast

“…The first is a lack of synergism between the cytotoxic agents, despite preclinical and clinical studies (17) 4 (3) that demonstrate synergism between UFT® and cisplatin [31,32], A second possibility is that the modulation ofUFT® by leucovorin does not work in patients with NSCLC. Ac tually, whether the combination of cisplatin and fluoropyrimidines modulated with leucovorin is active for the treatment of NSCLC remains undefined, and in vitro studies show contradictory results [30,33], Sugimoto et al [33] observed that inhibition of thymidylate synthase after 5-FU treatment did not correlate with the DNAdirected activity of 5-FU. If Sugimoto's in vitro results correlate well with clinical activity, therapy with 5-FU modulated with leucovorin might not be useful for the treatment of NSCLC [33], However, the combination of cisplatin/5-FU/leucovorin achieved a 41% response rate in one trial [14], Finally, dose reduction may be one cause of the low response to this regimen.…”

“…Ac tually, whether the combination of cisplatin and fluoropyrimidines modulated with leucovorin is active for the treatment of NSCLC remains undefined, and in vitro studies show contradictory results [30,33], Sugimoto et al [33] observed that inhibition of thymidylate synthase after 5-FU treatment did not correlate with the DNAdirected activity of 5-FU. If Sugimoto's in vitro results correlate well with clinical activity, therapy with 5-FU modulated with leucovorin might not be useful for the treatment of NSCLC [33], However, the combination of cisplatin/5-FU/leucovorin achieved a 41% response rate in one trial [14], Finally, dose reduction may be one cause of the low response to this regimen. In fact, the response rate in patients receiving full doses was 25%, which is similar to that seen by other investigators with cisplatin/5-FU/leucovorin [34,35], Whatever the reasons, the results achieved with our regimen do not allow us to recommend its further study in the treatment of advanced NSCLC.…”

Phase II Study with Folinic Acid, Etoposide, 5-Fluorouracil and Cisplatin (FLEP) for Advanced Gastric Cancer

“…In order to improve the efficacy of ELF, we added cisplatin because it is one of the most active agents in gastric cancer [9,10] and because it works synergistically with folinic acid/ 5-fluorouracil (5-FU) [11,12] and with etoposide [13] in experi mental tumors. Furthermore, there is a lack of cross resistance between these agents in vitro [14,15] and in vivo [16], Based on this background, we investigated in a phase I study the recommended dose of cisplatin ]P) that can be adminis tered together with a slightly modified ELF regimen. In this study.…”