Temozolomide, a methylating agent with clinical activity against
brain tumors, demonstrated excellent antitumor activity following p.o. administration to athymic mice bearing human
brain tumor xenografts. In the early stage s.c. implanted SNB-75
astrocytoma model, a 400-mg/kg dose administered on Day 5 produced 10 of 10 Day 54
tumor-free mice. In later staged s.c. U251 and SF-295
glioblastoma models, a single 600-mg/kg dose produced 9 of 10 Day 86 and 2 of 10 Day 40
tumor-free mice, respectively. In the latter group, a
tumor growth delay of > 315% was attained. Similar levels of activity were attained with equal total doses on schedules of daily for 5 doses and every fourth day for 3 doses. A single 40-mg/kg i.v. dose of
1,3-bis(2-chloroethyl)-1-nitrosourea (
BCNU) also demonstrated excellent activity, producing 9 of 10
tumor-free mice in the SNB-75 model and growth delays of 283 and 301% in the U251 and SF-295 models, respectively.
Temozolomide was also highly effective against intracerebral implants of the U251 and SF-295
glioblastomas. Administration of either 600 mg/kg on Day 1 or 200 mg/kg on Days 1, 5, and 9 produced 7 of 9 Day 90
tumor-free mice in the U251 model. In the SF-295 model, a single 400-mg/kg dose or three 200-mg/kg doses produced 3 and 4 of 10 Day 90
tumor-free mice, respectively, and prolonged survival by 127%. A single 40-mg/kg i.v. dose of
BCNU was more effective than
temozolomide in the intracerebral SF-295 model, and less effective in the intracerebral U251 model. The synergistic potential of
temozolomide and
BCNU in combination was evaluated in an advanced stage s.c. implanted SF-295 model. When
temozolomide was administered 2 h after
BCNU on a single treatment day, a dramatic synergistic
therapeutic effect was observed in two experiments. For example, single agent doses of
temozolomide (600 mg/kg) and
BCNU (60 mg/kg) and a combination (400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced growth delays of 190, 258, and > 492% (includes 5 of 10 Day 51
tumor-free mice), respectively. Analysis of the data by a quadratic dose response model indicated synergism with significance at P = 0.0001 in both experiments. Synergism also was demonstrated by the isobole method. The reverse sequence was more toxic, but at lower combination doses a synergistic effect was still observed (P = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)