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Esters of Chlorohydroxyacetone in Chemotherapy of Murine Tumors¹

Department of Biology, Syracuse University, Syracuse, New York 13210

1-Deoxyhalo analogs of dihydroxyacetone and of DL-glycerol were tested for cytostatic effects in vitro against dividing cell lines of murine L1210 leukemia and Ehrlich carcinoma, against primary stationary Ehrlich cells in vitro, and for in vivo chemotherapeutic effects against a number of murine tumors. Benzoate, p-nitrobenzoate, and 3,5-dinitrobenzoate esters of 1-chloro-3-hydroxyacetone inhibited proliferation in log-phase cultured cells by 50% at concentrations between 2 and 4 µM and inhibited thymidine incorporation by 50% into stationary cells at 60 to 150 µM. Comparable in vitro activities were obtained with the acetate ester and with chloroacetone. Corresponding glycerol analogs and the fluoro analogs in either the glycerol or dihydroxyacetone series were inactive. Chlorohydroxyacetone benzoate, chlorohydroxyacetone p-nitrobenzoate, and chlorohydroxyacetone 3,5-dinitrobenzoate produced 50 to 100% cure of 2.5 x 10⁷ Ehrlich tumor cell challenges in C57Bl/6 x DBA/2F₁ (hereafter called B6D2F₁) hosts with only a single drug injection, but only if the hosts were immunocompetent. The 3,5-dinitrobenzoate ester was the most effective, while the acetate ester was only weakly active and neither the phosphate ester nor chloroacetone was active in vivo. Chlorohydroxyacetone 3,5-dinitrobenzoate produced significant increases in life span and a number of long-term cures of P815 mastocytoma in semisyngeneic B6D2F₁ hosts, but had no effect in syngeneic DBA/2 hosts. The analog was inactive against L1210 leukemia, EL4 lymphoma, and CaD2 mammary adenocarcinoma in B6D2F₁ semisyngeneic hosts. Tumor-bearing treated animals were able completely to resist an added normally lethal tumor challenge given as soon as 24 hr after single-drug injection chemotherapy. After initial tumor challenge and single-injection treatment, viable tumor cells were recovered from treated animals that were lethal to naive passive recipients, even though cagemates of the treated tumor cell donors were cured. These results show that chlorohydroxyacetone benzoate esters are chemotherapeutically active in vivo under conditions that suggest drug-induced alteration of host-tumor interaction after initial direct cytotoxicity. Such results are consistent with previously obtained altered host response to murine Friend erythroleukemia cells treated in vitro with these same agents. It is not yet known whether the mechanisms responsible for the in vitro alteration of erythroleukemia cells are related to in vivo chemotherapy obtained in this work with Ehrlich tumor cells.

¹ This work was supported by USPHS Research Grant CA-10250 from the National Cancer Institute.

² Present address: Mayo Clinic, Rochester, Minn. 55901.

³ Present address: Department of Microbiology, University of California, Los Angeles, Calif. 90024.

⁴ Recipient of USPHS Career Development Award CA-70332 from the National Cancer Institute. To whom requests for reprints should be addressed, at Department of Biology, Syracuse University, 108 College Place, Syracuse, N.Y. 13210.

Received 3/ 6/78. Accepted 6/11/80.