Treatment > Carmustine / Temozolomide Investigations

Abstract

Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea

Plowman J, Waud WR, Koutsoukos AD, Rubinstein LV, Moore TD, Grever MR

Developmental Therapeutics Program, National Cancer Institute, Bethesda, Maryland 20892

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)

PMID: 8033099 [PubMed - indexed for MEDLINE]