This application is to study the pharmacodynamics (concentration-exposure time-effect relationship) of taxol, alone and in combination with other agents and/or radiation, in human solid tumors. These studies will be done using histocultures of breast, ovarian, head and neck and prostate tumors from individual patients. Taxol has shown activity in breast, ovarian and head and neck cancers. Earlier trials in prostate cancer using suboptimal doses show little activity in this disease.
Aim 1. Evaluate the pharmacodynamics of taxol as a single agent.
Aim 2. Evaluate the pharmacodynamics of taxol in combination with DDP or doxorubicin. These combinations are being or will be evaluated clinically. We will evaluate whether these combinations produce antagonistic, additive or synergistic effects, and whether these effects are schedule, sequence and concentration dependent.
Aim 3. Evaluate the pharmacodynamics of taxol in combination with radiation. This combination is being considered for clinical evaluation in head and neck cancer.
Aim 4. Compare the pharmacodynamics of taxol in primary and nodal metastatic tumors.
Aim 5. Assess the correlation of DNA ploidy, primary tumor site, grade and stage of the tumor, and previous treatment with the tumor response to taxol and taxol-containing combinations. The proposed studies address several key issues in the clinical use of taxol. These studies are timely in view of the extensive ongoing clinical evaluation of different taxol treatment schedules and taxol-containing combinations. We anticipate the data to indicate for human breast, ovarian, head and neck and prostate tumors, (a) the concentration (dose) dependency of taxol activity, (b)the schedule dependency, (c) the sequence dependency of combinations of taxol with other drugs and radiation, (d) whether taxol alone or taxol-containing combinations, at maximally tolerated concentrations, is more effective and (e) whether the primary and metastatic tumors from the same patients respond differently to taxol. The pharmacodynamic data in prostate tumors may indicate if the response can be enhanced substantially at higher drug concentration and, hence, whether additional clinical trials at the maximally tolerated doses are warranted.
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