Paclitaxel (Texol; Bristol-Myers Squibb Company, Princeton, NJ) and concurrent radiation (paclitaxel/RT) are being actively evaluated as treatment for locally advanced lung, pancreatic, and gastric cancers. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to synchronize cells at G2M, the most radiosensitive phase of the cell cycle. Because G2M arrest is necessary but not sufficient for paclitaxel radiosensitization, other cellular factors must interact with paclitaxel to produce radiosensitization. We have investigated whether molecular genetic alterations that disturb cell cycle regulation in tumor cells affect the action of paclitaxel as a radiosensitizer. The p53 tumor suppressor gene serves a critical role at the G1S transition of the cell cycle by blocking entry into S phase under conditions that would result in genetic instability. Mutations in the tumor suppressor gene, p53, confer resistance to radiation therapy and most chemotherapeutic agents, including cisplatin and 5-fluorouracil. In striking contrast, we have now shown that p53 mutations in non-small cell lung cancer do not confer resistance to paclitaxel/RT. The effect of p53 mutations on response to paclitaxel/RT in pancreatic and gastric cancers is currently being investigated. Knowledge of specific genetic alterations in individual tumors may permit the selection of optimal therapeutic strategy for individual patients.
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging
- Cancer Research