Treatment of tumours with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide.

The ability of WR-2721 [S-2(3-aminopropylamino)ethyl-phosporothioic acid] to selectively protect the host against the toxic effects of multiple doses of cis-dichlorodiammineplatinum [cis-Pt] or cyclophosphamide [CY] has been studied in mice and rats bearing 3 different tumours. Selective protection against cis-Pt induced nephrotoxicity has been demonstrated under all conditions studied, with the extent of protection being inversely related to the size of the cis-Pt dose. For example, pre-treatment with 200 mg/kg of WR-2721 30 min before each weekly dose of 2 mg/kg of cis-Pt allows the administration of this cytotoxic agent for 3 times longer before nephrotoxic injury. In none of these studies was there tumour protection. The same pattern was observed with CY, but quantitation of the extent of marrow protection was not possible for the multiple treatment studies, due to the longer latent period between induced and observed death with this drug. We conclude, therefore, that for both of these drugs, selective protection of the kidney and marrow is not only maintained under conditions of multiple treatment, but actually enhanced due to the need for smaller doses of cytotoxic agents in these protocols

Multicellular tumour spheroids: a model for combined in vivo/in vitro assay of tumour immunity.

Multicellular tumour spheroids (MTS) from 4 mouse tumours (Line 1 lung carcinoma; a fibrosarcoma, FSA; a mammary carcinoma, MCa-11; and SV40-transformed fibroblasts, SV-A31) WEre injected into the abdominal cavity of normal, immunized or tumour-bearing syngeneic mice, recovered after 4-48 h, and their growth measured in vitro for 7-16 days. Both normal and immunized mice inhibited MTS growth, but there was no correlation between the two types of inhibition, suggesting that different immunological processes were involved. For example, the greatest inhibition by normal mice was seen for the weakly immunogenic MCa-11, and the highly immunogenic tumour, SV-A31, was only moderately inhibited. However, the summed inhibition of MTS growth in normal and sensitized hosts corresponded to the behaviour of tumours as s.c. transplants; i.e., was inversely related to the malignancy of the same tumours. The inhibition of MTS by mice bearing identical early tumours (FSA or MCa-11) was comparable to that in immunized mice. Histological sections of SV-A31 MTS in normal or immunized hosts revealed the infiltration of MTS by various types of host cells, mostly polymorphonuclears, macrophages and lymphocytes