Studies in mice treated with ICRF-159 combined with daunorubicin or doxorubicin

We have investigated the effect of ICRF-159 on the toxicity of daunorubicin (DR) and doxorubicin (DX) given iv, and the effectiveness of ICRF-159 combined with DR or DX on the growth of transplantable MLV-M (murine leukemia virus-Moloney) leukemia, MS-2 solid sarcoma, and pulmonary MS-2 metastases in mice. The injection of ICRF-159 concurrently with the administration of DR resulted in a marked decrease in the toxicity of the antibiotic. However, when DX was injected concurrently with ICRF-159 an increase in antibiotic toxicity was observed, except when ICRF-159 was employed at a very low dosage. ICRF-159 administered alone did not influence the tumor growth in the systems tested and did not result in antimetastatic activity. In mice bearing transplanted MLV-M leukemia, the effects of the combination of ICRF-159 with DR or DX were not superior to those of DR or DX treatment on either tumor growth or lifespan. The treatment of MS-2 tumor with the ICRF-159 and DX combination neither produced a therapeutic synergism (therapeutic response superior to the maximum response obtainable by either agent independently) nor antagonized the antineoplastic action of DX. A marked inhibition of tumor growth and increase in lifespan were observed in the mice treated with a high dose of DR (10 mg/kg/injection) plus ICRF-159 (50 mg/kg/injection). We have also examined, on MS-2 lung metastases, the effectiveness of surgical-adjuvant combination chemotherapy with DR or DX plus ICRF-159 injected at different times with respect to surgery. A synergistic effect of DX or DR with ICRF-159 was observed when the drug treatment was performed before the surgery, or both before and after the surgery. No synergistic effect of DX or DR with ICRF-159 on MS-2 lung metastases was found when the MS-2 lung metastases were treated after the surgery. A higher antimetastatic activity was observed in the groups treated with a combination of toxic doses of DR and ICRF-150 than in the groups treated with a combination of toxic doses of DR and ICRF-159 than in the groups treated with tolerated doses of the antibiotic.