Tumor-associated macrophages stimulate the proliferation of murine tumor cells surviving treatment with the oncolytic cyclophosphamide analogue ASTA Z-7557:In vivo implications

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Abstract
This report is concerned with the hypothesis that tumor-associated macrophages (TAM) present during cyclophos-phamide (CY)-induced tumor regression stimulate proliferation of tumor stem cells that remain after the oncolytic action of CY has dissipated. In preliminary studies, plasma or serum from CY-injected mice was used as a source of CY metabolites. However, because of the relatively high background toxicity of normal mouse plasma/serum and the lack of a precise technique to quantify how much metabolite was present at any one time, this approach was abandoned. In place of the plasma metabolites, we used the CY analogue, 4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt, Asta Z-7557. On solubilization in water, Asta Z-7557 yields phosphoramide mustard, one of the oncolytic metabolites of CY in vivo. This approach enabled us to quantitate the amount of drug used in vitro and to control the amount to which tumor cells and macrophages were exposed. It was demonstrated that when two different C57BL/6J tumor cell targets, the MCA/76-9 sarcoma and the EL4 lymphoma subline, E2G.2, were treated with defined quantities of Asta Z-7557, those cells surviving the toxic effects were stimulated to proliferate in the presence of TAM isolated from the MCA/76-9 sarcoma. Although pretreatment of the TAM with the drug slightly diminished the stimulatory effect, this was still significantly greater than the effect of culture medium alone. In no instance was there evidence that drug treatment rendered the macrophages cytotoxic towards the tumor cells. The data supported the notion that in vivo the presence of a high proportion of TAM during CY-induced temporary tumor regression may contribute directly to the resurgence of tumor growth.