Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel.
Paclitaxel is a chemotherapeutic agent with potent microtubule stabilizing activity that arrests cells in G2-M. Because G2 and M are the most radiosensitive phases of the cell cycle, paclitaxel has potential as a cell cycle-specific radiosensitizer. In this study, we investigated the ability of paclitaxel to increase tumor radioresponse in vivo using a murine mammary carcinoma and the dependency of this response on accumulation of tumor cells in mitosis. Mice bearing 8-mm tumors were treated with paclitaxel (60 mg/kg i.v.), 9, 15, or 21 Gy of single-dose radiation, or with a regimen of both agents in which radiation was given 1, 9, or 24 h after paclitaxel. The effect of the treatments was determined by tumor growth delay. Microscopically, the percentage of mitotically arrested cells was only 4% 1 h after treatment with paclitaxel, increased to a maximum value of 30% at 9 h, and decreased to 12% 24 h after paclitaxel. Paclitaxel enhanced tumor radioresponse by factors of 1.21 to 2.49. The degree of enhancement increased with increases in both the dose of radiation and the time between paclitaxel administration and radiation delivery. Radiation efficiently destroyed mitotically arrested cells by apoptosis. The greatest enhancement of radiation response was not at the time of the highest mitotic arrest but at 1 day after paclitaxel treatment, showing that paclitaxel potentiates tumor radioresponse by mechanisms in addition to blocking the cell cycle in mitosis, possibly by tumor reoxygenation. Thus, these results show that paclitaxel is a potent in vivo radiopotentiating agent and has the potential to be usefully combined with radiotherapy.
Milas
L
L
Department of Experimental Radiotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Hunter
N R
NR
Mason
K A
KA
Kurdoglu
B
B
Peters
L J
LJ
D000818:Animals; D017209:Apoptosis; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D017239:Paclitaxel / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel