The overall objective of the contract is to identify, in a preclinical setting, therapeutically synergistic antitumor drug combinations that can be further evaluated in clinical trials. In order to accomplish this objective, the preclinical antitumor activity of single agents and any combination of cytotoxic antitumor agents, biological response modifiers or a biochemical modulator will be compared to determine whether any combination is more efficacious than the individual agents comprising the combination. The majority of the experiments will be conducted in vivo, but on occasion it will be more appropriate to conduct preliminary in vitro evaluations in order to gain insight into the potential synergy of the combination and/or the importance of sequencing of the agents. The in vivo models selected for the studies will be dependent upon the compounds to be evaluated. As appropriate, the models will utilize either murine tumors or human tumor xenografts growing in pathogen-free immune-competent or immune- deficient (e.g., athymic, SCID) mice. Once an additive or synergistic combination has been identified, additional studies may be conducted to confirm the effect in a second model and/or to optimize the therapeutic response through modification of either dosage ratio, schedule, sequencing and/or timing.
| Plowman, J; Waud, W R; Koutsoukos, A D et al. (1994) Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 54:3793-9 |
