AbstractThe potential role of transforming growth factor- in in vivo resistance was examined by administration of transforming growth factor--neutralizing antibodies to animals bearing the EMT-6/Parent tumor or the antitumor alkylating resistant tumors, EMT-6/CTX or EMT-6/CDDP. Treatment of tumor-bearing animals with anti-TGF- antibodies by intraperitoneal injection daily on days 08 post-tumor cell implantation increased the sensitivity of the EMT-6/Parent tumor to cyclophosphamide (CTX) and cisplatin (CDDP) and markedly increased the sensitivity of the EMT-6/CTX tumor to CTX and the EMT-6/CDDP tumor to CDDP, as determined by tumor cell survival assay. Bone marrow granulocyte-macrophage colony-forming units (CFU-GM) survival was determined from these same animals. The increase in the sensitivity in the tumors upon treatment with the anti-TGF- antibodies was also observed in increased sensitivity of the bone marrow CFU-GM to CTX and CDDP. Treatment of non-tumor-bearing animals with the anti-TGF- regimen did not alter blood ATP or serum glucose level but did decrease serum lactate levels. This treatment also decreased hepatic glutathione, glutathione S-transferase, glutathione reductase, and glutathione peroxidase in non-tumor-bearing animals by 4060% but increased hepatic cytochrome P450 reductase in these normal animals. Animals bearing the EMT-6/CTX and EMT-6/CDDP tumors had higher serum lactate levels than normal or EMT-6/Parent tumor-bearing animals; these were decreased by the anti-TGF- regimen. Treatment of animals bearing any of the three tumors with the anti-TGF- regimen decreased by 3050% the activity of hepatic glutathione S-transferase and glutathione peroxidase, and increased by 3580% the activity of hepatic cytochrome P450 reductase. In conclusion, treatment with transforming growth factor--neutralizing antibodies restored drug sensitivity in the alkylating agent-resistant tumors, altering both the tumor and host metabolic states.