Nitrosoureas are among the most widely used agents used in the treatment of
malignant gliomas. Here, the activity of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (
SarCNU) was compared with that of 1,3-bis-(2-chloroethyl)-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,
SarCNU, 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 (> or =20%
body weight loss). With a similar dosing schedule,
BCNU produced no
tumor-free animals, six regressions, and one
drug-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,
SarCNU similarly demonstrated antitumor activity that was superior to that of
BCNU. In the U-251 CNS
tumor model,
SarCNU yielded six of six
tumor-free animals at 80 mg/kg/dose with i.p. administration q.d. for 5 days, starting on day 14, whereas
BCNU, at 9 mg/kg/dose, yielded three of six
tumor-free mice and one
drug-related death. Again,
SarCNU resulted in
tumor-free animals at 66 and 45% of its optimal dose and was relatively nontoxic, in contrast to
BCNU. Results of testing to date indicate that
SarCNU is clearly more effective than
BCNU against the human CNS
tumors SF-295 and U-251 in vivo. These results encourage the initiation of clinical trials for
SarCNU, in an effort to improve therapeutic approaches to
glioma, but clinical trials must determine whether superiority of
SarCNU in preclinical models can be extrapolated to patients.