Docetaxel enhances tumor radioresponse in vivo.
Although the radiosensitizing potential of paclitaxel has been investigated extensively in cancer treatment, a sister taxane, docetaxel, has been studied rarely. We investigated the ability of docetaxel to enhance in vivo tumor radioresponse and influence radiation injury to normal tissue. In addition, mitotic arrest and apoptosis in tumors and normal tissues were assessed after docetaxel administration to determine whether these cellular effects underly its radio-modifying action. Mice bearing in their legs 8-mm isotransplants of a murine mammary carcinoma, designated MCA-4, were treated with 33 mg/kg docetaxel i.v., 9-21 Gy single-dose local tumor irradiation, or both (in which case radiation was given 9 or 48 h after docetaxel). Tumor growth delay was the end point of the treatments. Mitotic arrest and apoptosis were assayed 1-72 h after treatment with docetaxel. Normal tissue radioresponse was determined using jejunal crypt cell survival 3.5 days after mice were exposed to 9.2-14.8 Gy single-dose, total-body irradiation; the mice were treated with 33 mg/kg docetaxel i.v. 3, 9, or 48 h before irradiation. Docetaxel was assessed for its ability to induce mitotic arrest and apoptosis in jejunum 1-72 h after treatment. Docetaxel induced both mitotic arrest and apoptosis in both tumor and jejunum. Mitotic arrest preceded apoptosis and peaked in the tumor at 9-12 h after treatment; it peaked at 3 h in jejunum. Docetaxel enhanced tumor radioresponse by a factor of 1.45 when the drug was given 9 h before radiation and 2.33 when it was given 48 h before. In contrast, it only slightly enhanced radiation-induced damage of the jejunum and only when given 3 or 9 h before irradiation. Thus, docetaxel given within 2 days before irradiation acted as a potent enhancer of tumor radioresponse and increased the therapeutic gain of irradiation.
Mason
K A
KA
Departments of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Hunter
N R
NR
Milas
M
M
Abbruzzese
J L
JL
Milas
L
L
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D000077143:Docetaxel; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D007583:Jejunum; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D043823:Taxoids; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel