PRECLINICAL ANTITUMOR-ACTIVITY OF TEMOZOLOMIDE IN MICE - EFFICACY AGAINST HUMAN BRAIN-TUMOR XENOGRAFTS AND SYNERGISM WITH 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA
J. Plowman et al., PRECLINICAL ANTITUMOR-ACTIVITY OF TEMOZOLOMIDE IN MICE - EFFICACY AGAINST HUMAN BRAIN-TUMOR XENOGRAFTS AND SYNERGISM WITH 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA, Cancer research, 54(14), 1994, pp. 3793-3799
Temozolomide, a methylating agent with clinical activity against brain
tumors, demonstrated excellent antitumor activity following p.o. admi
nistration to athymic mice bearing human brain tumor xenografts. Is th
e early stage s.c. implanted SNB-75 astrocytoma model, a 400-mg/kg dos
e administered on Day 5 produced 10 of 10 Day 54 tumor-free mice. In l
ater 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, re
spectively. In the latter group, a tumor growth delay of >315% was att
ained. 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 (BC
NU) 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 U25
1 and SF-295 models, respectively. Temozolomide was also highly effect
ive against intracerebral implants of the U251 and SF-295 glioblastoma
s. 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 pr
oduced 3 and 4 of 10 Day 90 tumor-free mice, respectively, and prolong
ed survival by 127%. A single 40-mg/kg i.v. dose of BCNU was more effe
ctive than temozolomide in the intracerebral SF 295 model, and less ef
fective in the intracerebral U251 model. The synergistic potential of
temozolomide and BCNU in combination was evaluated in an advanced stag
e s.c. implanted SF-295 model. When temozolomide was administered 2 h
after BCNU on a single treatment day, a dramatic synergistic therapeut
ic effect was observed in two experiments. For example, single agent d
oses of temozolomide (600 mg/kg) and BCNU (60 mg/kg) and a combination
(400 mg/kg + 27 mg/kg) demonstrating equivalent toxicity produced gro
wth 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 exp
eriments. Synergism also was demonstrated by the isobole method. The r
everse sequence was more toxic, but at lower combination doses a syner
gistic effect was still observed (P = 0.0001). Using the quadratic mod
el, no confirmed modulation of the antitumor activity of temozolomide
was demonstrated by i.p. administration of either 10 or 30 mg/kg O-6-b
enzylguanine 1 h before or 1 h after temozolomide. These data provide
a rationale for the clinical evaluation of temozolomide and BCNU combi
nations in patients with brain tumors.