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Experimental Antitumor Activity against Murine Tumor Model Systems of 8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide), a Novel Broad-Spectrum Agent¹

Cancer Research Campaign Experimental Chemotherapy Group, Department of Pharmaceutical Sciences, Aston University, Birmingham B4 7ET, England [J. A. H., M. F. G. S., S. P. L., N. W. G.]; Rhóne-Poulenc Santé, Centre de Recherches de Vitry, 94407, Vitry Sur Seine Cedex, France [C. F., F. L.]; Institut Jules Bordet, 1000 Bruxelles, Belgium [G. A.]; and May and Baker, Ltd., Dagenham, Essex RM10 7XS, England [E. L., R. M. T.]

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (mitozolomide) demonstrates curative action against a range of murine tumor model systems. At single doses of between 20 and 40 mg/kg, the latter of which approximates the 10% lethal dose value in mice, the compound elicited cures against the L1210 and P388 leukemias irrespective of the route of tumor and/or drug administration; in these tests, animals receiving 10⁵ cells i.p. survived >60 days after treatment. Potent effects were also observed against the TLX5 lymphoma (s.c.) and B16 melanoma (i.p.). In other experiments, 7 of 10 animals implanted with 2 x 10⁵ Lewis lung carcinoma cells survived >60 days while 10 of 10 animals survived >60 days after implantation of the Colon 26 tumor. Potent inhibition of the solid tumor models was also observed with complete cures of the Colon 38, M5076 sarcoma, and ADJ/PC6A plasmacytoma. In cross-resistance studies, the compound was ineffective against an L1210 leukemia made resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea and against a TLX5 lymphoma resistant to dimethyltriazenes but cured animals bearing the L1210 leukemia with derived resistance to cyclophosphamide.

¹ This is Part 6 of the series "Antitumor Imidazotetrazines" (Part 5 is ref. 7).

² Recipient of grants from the Cancer Research Campaign, United Kingdom, in partial support of this research.

³ To whom correspondence and requests for reprints should be addressed.

⁴ Recipient of a grant from the Science and Engineering Research Council, in partial support of this work. Present address, Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205.

⁵ Recipient of National Cancer Institute Contract N01-CM-07350, under which antitumor results from the Institut Jules Bordet were obtained.

Received 6/ 6/84. Revised 11/19/84. Revised 2/27/85. Accepted 3/ 4/85.

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