Maximum tolerable doses of intravenous zldovudlne in combination with 5-fluorouracil and leucovorin in metastatlc colorectal cancer patients Clinical evidence of significant antitumor activity and enhancement of zidovudine-induced DNA single strand breaks in peripheral nuclear blood cells

A. Falcone, M. Lencioni, I. Brunetti, E. Pfanner, G. Allegrini, A. Antonuzzo, M. Andreuccetti, G. Malvaldi, R. Danesi, M. Del Tacca, P. F. Conte

Research output: Contribution to journalArticle

Abstract

Background: Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU -f- 1-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells. Patients and methods: Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/rrr i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding. Results: Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered évaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (957., confidence limit interval 26%64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FL' + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LVand AZT was found to be cumulative. Conclusions: These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FL + LV warrants further study in colorectal cancer.

Original languageEnglish
Pages (from-to)539-545
Number of pages7
JournalAnnals of Oncology
Volume8
Issue number6
Publication statusPublished - 1997

Keywords

  • AZT
  • DNA
  • Fluorouracil
  • Phase II
  • Strand breaks
  • Zidovudine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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