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MS- 2 tumor produced in BALB/c mice by transplant of in vitro cultivated cells derived from a primary MSV-M tumor in mice did not show spontaneous regression but grew progressively and killed the host. The MS- 2 tumor was histologically classified as a malignant sarcoma. In syngeneic BALB/c mice, the i.m. transplanted MS- 2 tumor had a mean doubling time of 2.5 days when the tumor mass was 500 mg and 14 days when the tumor reached 4.0 g . MS- 2 tumor cells showed a high ability to metastatize (tested by bioassay). The organ mainly involved was the lung. In a small percentage of mice, metastases were also detected in spleen, liver, kidney, brain and blood. The activity of: cyclophosphamide, daunorubicin, adriamycin and 4 ′-epi-adriamycin on the MS- 2 tumor was evaluated. The effects on both tumor growth and pulmonary metastases were detected. In parallel, the drugs were tested on the highly immunogenic T-MSV tumor, obtained by serial. in vivo passages of the primary MSV-induced tumor. Daunorubicin did not have any therapeutic effect on the growth of MS- 2 tumor; adriamycin produced a marked delay of the tumor growth and a significant increase of the life span; cyclophosphamide produced a longer delay in tumor growth than adriamycin did, but the life span was only slightly increased. On the T-MSV tumor, daunorubicin and adriamycin reduced tumor growth and did not affect spontaneous tumor regression; cyclophosphamide reduced tumor growth but completely abolished the spontaneous regression. Adriamycin and its new derivative 4 ′-epi-adriamycin, given to mice in which the MS- 2 tumor had been surgically removed, inhibited the presence of tumor cells at the lung level. The MS- 2 tumor studied in parallel with the T-MSV tumor allows the comparison of drug activity on a highly or weakly immunogenic tumor. Moreover, the MS- 2 tumor is a viable model for studying the activity of chemotherapeutic drugs on lung metastases and their adjuvant effect on surgery.

The MS-2 tumor behaved like human spontaneous tumor: slow and progressive growth, extensive dissemination, high capacity to metastasize to the lung and low antigenicity. The chemotherapeutic sensitivity of MS-2 sarcoma and the antimetastatic activity of some clinically active antineoplastic drugs administered alone or in combination, or in surgical-adjuvant chemotherapy studies were investigated. Significant inhibition of tumor growth was obtained with: melphalan (ME), cyclophosphamide (CY), BCNU, adriamycin (AD), daunorubicin (DR) and bleomycin (BL). ME and BCNU showed activity in reducing the percentage of mice with metastatic activity of some clinically active antineoplastic drugs administered alone or tumors in conjunction with surgery drastically reduced the number of mice with lung foci. This treatment was found to be more effective on pulmonary metastases than was surgery and single-drug therapy. The antimetastatic activity of adjuvant chemotherapy with AD plus ICRF-159 supplied at different times with respect to surgery was also examined. A synergistic effect was observed on lung metastases when the treatment was performed before the surgery; when the combined treatment was performed after the surgery, a lower synergistic effect was found.

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.