Most effective route of administration and utilization of high-dose chemotherapy with bone marrow transplantation in...

In order to find out which anticancer drugs could utilize to the best advantage a syngeneic bone marrow transplantation in high-dose chemotherapy for cancer, we tested six drugs [nimustine hydrochloride (ACNU), Adriamycin, cyclophosphamide (CY), mitomycin c, vindesin, etoposide] in Sprague-Dawley rats from a standpoint of the beneficial effect of bone marrow transplantation (BMT). Two or three varying doses of each drug were administered i.v. on Day 0, followed by the injection of syngeneic bone marrow (BM) cells (5 x 10(7), i.v.) on Day 2, and the animals were observed for over 60 days. Adriamycin caused high rates of peripheral neuropathy, and was therefore judged to be inappropriate for high-dose chemotherapy-BMT in this animal model. Among the other five drugs, a beneficial effect of BMT was observed only with CY (300-400 mg/kg) and ACNU (40 mg/kg). In order to enhance the beneficial effect of BMT observed with CY and ACNU, a way of drug administration was designed and carried out. Consequently a higher survival rate was obtained in the following experimental groups: (a) (CY 200 mg/kg, Days 0 and 1) + BMT greater than (CY 400 mg/kg, Day 0) + BMT, (ACNU 20 mg/kg, Days 0 and 1) + BMT greater than (ACNU 40 mg/kg, Day 0) + BMT. (b) (CY 200 mg/kg + ACNU 20 mg/kg, Day 0) + BMT greater than (CY 400 mg/kg or ACNU 40 mg/kg, Day 0) + BMT. (c) (CY 200 mg/kg, Day 0) + (ACNU 20 mg/kg, Day 1) + BMT greater than (ACNU 20 mg/kg, Day 0) + (CY 200 mg/kg, Day 1) + BMT. Among the six anticancer drugs tested in this study, CY and ACNU were suggested to be more appropriate drugs for high-dose chemotherapy-BMT, but methods for reducing drug toxicity (dose, combination, sequence) were necessary so as to enhance the beneficial effect of the BMT.