Effect of a Bovine Hemoglobin Preparation on the Response of the FSaIIC Fibrosarcoma to Chemotherapeutic Alkylating Agents

Polymerized bovine hemoglobin solutions (PBHS) are being actively investigated as blood substitutes. In studies analogous to those we conducted with perfluorochemical emulsions/carbogen, we have examined the effect of PBHS +/- carbogen (95% O2, 5% CO2) breathing on the antitumor efficacy of melphalan, cyclophosphamide, N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) and cis-diamminedichloroplatinum(II) (cis-platin). The tumor growth delay of the FSaIIC fibrosarcoma treated with melphalan (10 mg/kg), cyclophosphamide (150 mg/kg), cisplatin (10 mg/kg) and BCNU (15 mg/kg) was increased about 2.2-fold, about 2.1-fold, about 1.2-fold and about 1.5-fold, respectively, when PBHS (12 mg/kg) was administered i.v. before each drug was injected i.p. The tumor growth delay produced by each drug was further increased when carbogen breathing for 6 h was allowed after administration of the drug and PBHS. In tumor cell survival experiments 24 h following drug treatment, the addition of PBHS increased the tumor cell killing of both melphalan and cyclophosphamide by about a factor of 10 at the lowest doses of each drug tested (10 mg/kg for melphalan and 100 mg/kg for cyclophosphamide) compared to the drug alone. However, at higher drug doses this effect was lost. The toxicity of each antitumor agent toward bone marrow (granulocyte/macrophage-colony-forming units) was increased 2- to 3-fold by the combined treatment. These results suggest that use of PBHS +/- carbogen breathing may add significantly to the efficacy of antitumor alkylating agents, however, the in vivo/in vitro data suggest that there will be increased bone marrow toxicity with this approach. This needs to be taken into account in the design of clinical trials.