levoleucovorin and 1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea

In preparation for a phase II trial we performed a dose-finding study involving tauromustine (TCNU), fluorouracil (5-FU) and leucovorin (LV), applied in patients with colon cancer. To prevent TCNU/5-FU antagonism, a phenomenon recently demonstrated in vitro, special attention was paid to the sequencing of these agents.. In 25 patients with advanced colorectal carcinoma (13 M, 12 F, median age 51 yrs), four dose levels of TCNU (25, 30, 35 or 40 mg/m2) were investigated. The agent was administered orally once per week in weeks 1 through 4, in combination with fixed i.v. doses of 400 mg/m2 5-FU and 80 mg/m2 LV, once a week, weeks 1 through 8. Unless progression occurred, two 8-week cycles were applied. TCNU was administered at least 24 hours prior to 5-FU, because recent in vitro studies suggested that such an interval is required to obtain additive cytotoxicity.. All 25 patients were evaluable for toxicity; 23 patients received at least one full 8-week course, and 13 were eligible for second cycles. Significant haematologic toxicity, predominantly thrombocytopenia WHO grade 3 or 4, was mainly encountered at the 35 and 40 mg/m2 dose levels. Although occasionally severe, myelosuppression did not result in toxic deaths; spontaneous haemorrhage was never observed, and platelet transfusions were not required. Additional toxicity, also related to the two higher dose levels, consisted of diarrhea (WHO grade 3) and the 'hand and foot syndrome', both occurring in a single patient; two patients developed fever of undetermined origin, but only one of them required hospitalization and antibiotic treatment. The overall response rate was 20% (7 partial responses in 25 evaluable patients).. For phase II studies, we recommend a weekly oral dose of 40 mg/m2 TCNU, weeks 1 through 4, in combination with 400 mg/m2 5-FU and 80 mg/m2 LV (IV), once a week, weeks 1 through 8.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nitrosourea Compounds; Prognosis; Taurine

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nitrosourea Compounds; Taurine; Treatment Outcome

Despite recent advances in chemotherapy, the prognosis of advanced colorectal cancer remains poor. Although the taurine-based nitrosourea tauromustine (TCNU) has demonstrated schedule-dependent synergism with 5-fluorouracil (5-FU) and leucovorin (LV) against a variety of tumors in vitro, its efficacy relative to and in combination with these drugs in vivo remains unknown. To study this, BALB/C mice had C26 tumor implanted subcutaneously five days prior to the following treatment (doses and route of administration being the same in all groups): Group 1--no treatment; Group 2--TCNU (30 mg/kg by gavage); Group 3--LV (100 mg/kg intraperitoneally [IP]) and, one hour later, LV plus 5-FU (100 mg/kg IP); Group 4--LV and, one hour later, LV plus 5-FU and TCNU; and Group 5--TCNU and, on the following day, LV and, one hour later, LV plus 5-FU. All treatments were repeated seven days later. Body weight and tumor weight were measured twice weekly, and survival was noted. Postmortems were performed in all animals, and evidence of primary or secondary tumor was recorded. All surviving animals were sacrificed at 60 days. We found that 1) 87 percent of animals receiving TCNU and 60 percent of animals receiving LV, 5-FU, and TCNU survived to day 60; none of these animals had evidence of tumor when sacrificed; 2) animals in all other groups died by day 34; 3) evidence of metastases was found in five animals in Group 1 and one each in Groups 2 and 5; and 4) administering TCNU 24 hours prior to 5-FU plus LV resulted in death from toxicity in all animals. Thus, while synergism between TCNU and 5-FU plus LV was not seen, the antitumor properties of TCNU are significantly greater than those of conventional chemotherapy.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Leucovorin; Male; Mice; Mice, Inbred BALB C; Nitrosourea Compounds; Taurine