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Identification of Nonproliferating but Viable Hypoxic Tumor Cells in Vivo¹

Medical Biophysics Department, British Columbia Cancer Research Centre, Vancouver, British Columbia, V5Z 1L3 Canada [R. E. D.], and Department of Radiation Oncology and Toxicology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 [J. A. R.]

We have used the combination of pimonidazole labeling of hypoxic cells, bromodeoxyuridine labeling of proliferating cells, and cell sorting based on Hoechst 33342 perfusion to directly study hypoxia and proliferation in human tumor xenografts and transplantable murine tumors in vivo. Hypoxia was largely confined to cells in regions with the least perfusion, although in tumors exhibiting transient blood flow, hypoxic cells were not as highly localized. Similarly, proliferation and hypoxia were mutually exclusive except in areas of a tumor subjected to transient changes in perfusion. By determining the clonogenic potential, pimonidazole labeling intensity, and radiosensitivity of sorted tumor cell subpopulations, we have provided direct evidence that pimonidazole identifies hypoxic tumor cells of therapeutic relevance in vivo. Given that pimonidazole exhibits few diffusion or delivery problems and no apparent cytotoxicity, it appears to be a versatile and useful label for hypoxic cells in solid tumors.

¹ This work was supported by USPHS Grants CA-56600 (to R. E. D.) and CA-50995 (to J. A. R.) from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Medical Biophysics Department, British Columbia Cancer Research Centre, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3 Canada. Phone: 604-877-6047; Fax: 604-877-6002; E-mail: rdurand@bccancer.bc.ca.

Received 4/23/98. Accepted 6/25/98.

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