A comparison of radiosensitization by etanidazole and pimonidazole in mouse tumors.
Radiosensitization by pimonidazole (Ro 03-8799) was tested in three murine tumors, EMT6/SF using the excision assay, SCC-VII/SF using the excision and growth delay assays, and MDAH-MCa-4 using TCD50 assays with both single doses and 6 fractions of radiation with a 24-hr interfraction interval. Results were compared with those using etanidazole (SR-2508), both at equitoxic doses and at doses giving tumor concentrations similar to those achievable in the clinic. In excision assays with EMT6/SF and SCC-VII/SF tumors, pimonidazole and etanidazole gave similar radiosensitization at similar concentrations in the tumors. Pimonidazole, however, did not demonstrate radiosensitization in SCC-VII/SF tumors in the growth delay assay, despite tumor concentrations that gave maximum sensitization in the excision assay. Furthermore, pimonidazole gave less than expected sensitization in single dose and 6-fraction TCD50 assays with MDAH-MCa-4 tumors, and less sensitization than comparable levels of etanidazole in this tumor line. When the concentration of pimonidazole in the tumors was approximately 0.36 mumoles/g the dose modification factor (DMF = dose without sensitizer/dose with sensitizer to give an isoeffect) was 1.56 (1.40-1.74, 95% c.l.) in single dose TCD50 assays. Etanidazole, however, gave a DMF of 1.92 (1.59-2.32) with a tumor concentration of approximately 0.32 mumoles/g and 1.69 (1.46-1.96) with a tumor concentration of approximately 0.21 mumoles/g. Thus, etanidazole gave more consistent sensitization for different tumors and different endpoints than did pimonidazole. The results appear to confirm the disappointing performance of pimonidazole in the clinic.
Stone
H B
HB
Department of Radiation Oncology, University of California, San Francisco 94143.
Hirst
V K
VK
Cribbs
R
R
Luu
Y H
YH
Brown
J M
JM
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D017341:Etanidazole; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole