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 + l-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.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/m2 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.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 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 decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + 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 + LV and AZT was found to be cumulative.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-FU + LV warrants further study in colorectal cancer.

Maximum tolerable doses of intravenous zidovudine in combination with 5-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 nuclear blood cells / A., Falcone; M., Lencioni; I., Brunetti; E., Pfanner; G., Allegrini; A., Antonuzzo; M., Andreuccetti; G., Malvaldi; R., Danesi; M. D., Tacca; Conte, Pierfranco. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - STAMPA. - 8:(1997), pp. 539-545.

Maximum tolerable doses of intravenous zidovudine in combination with 5-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 nuclear blood cells.

CONTE, Pierfranco
1997-01-01

Abstract

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 + l-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.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/m2 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.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 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 decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + 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 + LV and AZT was found to be cumulative.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-FU + LV warrants further study in colorectal cancer.
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Maximum tolerable doses of intravenous zidovudine in combination with 5-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 nuclear blood cells / A., Falcone; M., Lencioni; I., Brunetti; E., Pfanner; G., Allegrini; A., Antonuzzo; M., Andreuccetti; G., Malvaldi; R., Danesi; M. D., Tacca; Conte, Pierfranco. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - STAMPA. - 8:(1997), pp. 539-545.
A., Falcone; M., Lencioni; I., Brunetti; E., Pfanner; G., Allegrini; A., Antonuzzo; M., Andreuccetti; G., Malvaldi; R., Danesi; M. D., Tacca; Conte, Pierfranco
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/739323
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