MAXIMUM TOLERABLE DOSES OF INTRAVENOUS ZIDOVUDINE IN COMBINATION WITH5-FLUOROURACIL AND LEUCOVORIN IN METASTATIC COLORECTAL-CANCER PATIENTS - CLINICAL-EVIDENCE OF SIGNIFICANT ANTITUMOR-ACTIVITY AND ENHANCEMENT OF ZIDOVUDINE-INDUCED DNA SINGLE-STRAND BREAKS IN PERIPHERAL NUCLEARBLOOD-CELLS

Background. Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytoto xicity. Phase I studies have demonstrated that the maximum tolerable d ose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + 1-leucovorin (LV), and that this combination has p romising antitumor activity. The purpose of this study was therefore t o evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, adm inistered al its MTD, and to determine whether 5-FU enhances AZT-induc ed DNA strand breaks in blood nuclear cells. Patients and methods. Twe nty-nine chemotherapy-naive metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a we ekly 5-FU 500 mg/m(2) i.v. bolus + LV 250 mg/m(2) i.v. two-hour infusi on + AZT 8000 mg/m(2) 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 genera lly 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 evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decre ased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT which reduced the p ercentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was foun d to be cumulative. Conclusions. These studies demonstrate that the pr esent dose and schedule of AZT in combination with 5-FU + LV has signi ficant activity in metastatic colorectal cancer and that the combinati on of 5-FU + LV with AZT increases the amount of DNA damage. Therefore , AZT in combination with 5-FU + LV warrants further study in colorect al cancer.