Measurement of sister chromatid exchange induction in intracerebral brain tumors as a method for evaluation of therapeutic drug combinations.
Rats with 9L or 9L-2 intracerebral brain tumors were treated with streptozotocin (STZ) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) at various doses either as single agents or in combination. Treatment of rats bearing 9L or 9L-2 tumors with either STZ or BCNU produced a significant increase the level of sister chromatid exchanges (SCEs) (p < .001). Compared with 9L-2 tumors, 9L tumors were 7.8-fold more sensitive to the induction of SCEs by BCNU treatment. After combination treatments of STZ and BCNU, the number of SCEs observed in 9L tumors was additive but was synergistic in 9L-2 tumors. O6-alkylguanine DNA alkyltransferase activity (AGT) was measured in 9L and 9L-2 cells in vitro. No AGT activity was detected in 9L cells, however, a low level of activity was measured in 9L-2. In vitro, treatment of 9L-2 cells with STZ produced a dose dependent inhibition of AGT activity. We interpret, these results to suggest that STZ pretreatment potentiated the effects of BCNU in 9L-2 tumors by inhibiting AGT activity. The observations in this study suggest that measurement of SCE induction in intracerebral tumor models may provide a useful strategy for evaluating the effectiveness of new agents and potential therapeutic combinations for the treatment of gliomas.
Bodell
W J
WJ
Brain Tumor Research Center of the Department of Neurological Surgery University of California, San Francisco 94143-0555, USA. bodell@itsa.ucsf.edu
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002330:Carmustine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005069:Evaluation Studies as Topic; D018316:Gliosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013311:Streptozocin / Q000627:therapeutic use*; D013687:Telencephalon
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D013311:Streptozocin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine