1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine(101M): A novel sulfonylhgdrazine prodrug with broad-spectrum antineoplastic activity

Our laboratory has synthesized and evaluated the anticancer activity of a n umber of sulfonylhydrazine DNA modifying agents. As a class, these compound s possess broad spectrum antitumor activity, demonstrating significant acti vity against a variety of experimental murine tumors, including the P388 an d L1210 leukemias, B16 melanoma, M109 long carcinoma, and M5076 reticulum c ell sarcoma, as well as against the human LX-I lung carcinoma xenograft. Th e current report describes the activity of a more recently synthesized memb er of this class, 1,2-bis(lnethylsulfonyl)-1-(2-chloroethyl)-2-(methylamino )carbonylhydrazine (101M). 101M was active in mice against the i,p. implant ed L1210 leukemia over a wide range of doses and produced long-term survivo rs when administered as a single i.p. bolus of 10, 20, 40, 60, or 80 mg/kg, demonstrating a wider margin of safety than the nitrosourea, 1,3-bis(2-chl oroethyl)-1-nitrosourea (BCNU). Curative therapy was achieved with doses of 101M that did not produce depression of the bone marrow. 101M was also hig hly effective against the L1210 leukemia when administered by the oral rout e. The ability of 101M to penetrate the blood-brain barrier and eradicate l eukemia cells in the brain was remarkable (>6 log kill). This agent was als o curative against L1210 variants resistant to cyclophosphamide, BCNU, or m elphalan. Mice implanted with the murine C26 colon carcinoma were also cure d by two injections of 10 or 20 mg/kg of 101M. Administration of 101M by tw o different well-tolerated regimens caused complete regression of establish ed human glioblastoma U251 xenografts in 100% of treated mice, and signific ant responses were also obtained with 101M against advanced murine M109 lun g carcinomas in mice. The broad spectrum of anticancer activity of the sulf onylhydrazine prodrug 101M coupled with the wide range of therapeutic safet y exhibited by this agent, makes 101M particularly attractive for further d evelopment and clinical evaluation.