Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse.
Paclitaxel is a novel chemotherapeutic agent that arrests cells in the radiosensitive G2 and M phases of the cell cycle and as such may act as a specific cell cycle radiosensitizer. We recently reported that paclitexel induces mitotic arrest in the MCA-4 murine mammary carcinoma and enhances radio-response of this tumor. However, the greatest enhancement was observed not when radiation was given at the time of peak mitotic arrest, which was 9 h after paclitaxel administration, but when it was given 24 h after paclitaxel. This implied the involvement of other mechanisms in radiosensitization; we hypothesized that tumor reoxygenation was a likely mechanism based on the observed massive loss of mitotically arrested cells at 24 h. The present study shows that paclitaxel greatly enhanced MCA-4 tumor radioresponse when radiation was given under air-breathing conditions (DMF = 1.74), but not when it was performed under hypoxic conditions. This observation supports the hypothesis of tumor reoxygenation as a mechanism of enhancement of tumor radioresponse. That reoxygenation occurred in tumors treated with paclitaxel 24 h earlier was confirmed by direct measurements of pO2 values, using the Eppendorf pO2 histograph. Median pO2 values increased from 6.2 mmHg in untreated tumors to 10.0 mmHg in tumors treated with paclitaxel. These observations emphasize the importance of timing of paclitaxel administration in relation to radiation treatment.
Milas
L
L
Department of Experimental Radiotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Hunter
N
N
Mason
K A
KA
Milross
C
C
Peters
L J
LJ
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D002588:Cesium Radioisotopes; D005720:Gamma Rays; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D010100:Oxygen / Q000032:analysis; D010101:Oxygen Consumption / Q000187:drug effects*; D017239:Paclitaxel / Q000627:therapeutic use*; D010313:Partial Pressure; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D002588:Cesium Radioisotopes; D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel; D010100:Oxygen