2-CHLOROETHYL-3-SARCOSINAMIDE-1-NITROSOUREA NOVEL CHLOROETHYLNITROSOUREA ANALOG WITH ENHANCED ANTITUMOR-ACTIVITY AGAINST HUMAN GLIOMA XENOGRAFTS

Nitrosoureas are among the most widely used agents used in the treatme nt of malignant gliomas, Here, the activity of 2-chloroethyl-3-sarcosi namide-1-nitrosourea (SarCNU) was compared with that of 1,3-bis-(2-chl oroethyl) -1-nitrosourea (BCNU), in vivo against s.c. implanted SF-295 and U-251 central nervous system (CNS) tumor xenografts. When given i .v., q4d for 3 doses, to athymic mice bearing s.c. SF-295 tumors, SarC NU, at an optimum of 167 mg/kg/dose, produced 9 tumor-free animals of 10 total animals, 1 regression, and no evidence of overt toxicity (gre ater than or equal to 20% body weight loss). With a similar dosing sch edule, BCNU produced no tumor-free animals, six regressions, and one d rug-related death at its optimum of 30 mg/kg/dose. Furthermore, SarCNU retained high antitumor activity at two lower dose levels, 66 and 45% of the optimal dose, whereas BCNU demonstrated a progressive loss of antitumor activity at lower doses. Following p.o. administration, SarC NU similarly demonstrated antitumor activity that was superior to that of BCNU, In the U-251 CNS tumor model, SarCNU yielded six of six tumo r-free animals at 80 mg/kg/dose with i.p. administration q.d. for 5 da ys, starting on day 14, whereas BCNU, at 9 mg/kg/dose, yielded three o f six tumor-free mice and one drug-related death. Again, SarCNU result ed in tumor-free animals at 66 and 45% of its optimal dose and was rel atively nontoxic, in contrast to BCNU. Results of testing to date indi cate that SarCNU is clearly more effective than BCNU against the human CNS tumors SF-295 and U-251 lit vivo. These results encourage the ini tiation of clinical trials for SarCNU, in an effort to improve therape utic approaches to glioma, but clinical trials must determine whether superiority of SarCNU in preclinical models can be extrapolated to pat ients.