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Dunning R3327-H and R3327-AT tumors growing subcutaneously in the flanks of Fischer X Copenhagen rats were irradiated with 137Cs gamma-rays at volumes of approximately 300 mm. The effects of various doses of radiation were estimated by measurements of subsequent tumor growth as well as by histological evaluation. The well-differentiated, hormonally-responsive R3327-H tumor was more radiosensitive than the anaplastic R3327-AT tumor. The reasons for this increased radiation sensitivity of the R3327-H tumor include a greater "apparent" radiation sensitivity of tumor cells and the absence of tumor hypoxia. The presence of hypoxic tumor stem cells was inferred from significant radiosensitization of tumor growth delay by 0.5 mg./gm. misonidazole and by a technique which utilizes radioactively-labelled misonidazole as a marker for hypoxic cells. The persistence of a mass of R3327-H tumor tissue after aggressive radiotherapy was not indicative of tumor cells. Furthermore, the rapid increase in volume of R3327-AT cells after aggressive radiotherapy was attributed to limited proliferation of tumor cells which were destined to ultimately die. Possible implications of these findings for the management of human prostatic adenocarcinoma are discussed.

Dunning R3327-AT prostate carcinomas growing in Fischer X Copenhagen rats were treated with interstitial photodynamic therapy (PDT--15 mg/kg Photofrin II 4 hours before illumination with 630-nm light via four parallelly implanted optical fibers) at different light intensities. Forty to 60 minutes after treatment, 31P-nuclear magnetic resonance spectra of tumors in anesthetized animals were obtained at 2.35 Tesla using surface coil localization. Areas under resonance peaks were normalized to the area under the peak of a phosphorus standard positioned at a fixed distance on the opposite side of the surface coil. Tumor concentrations of phosphomonoesters and phosphodiesters showed no change after tumor light doses up to 3000 J. Phosphocreatine, alpha-adenosine triphosphate (ATP), beta-ATP, and gamma-ATP signals decreased and inorganic phosphate signals increased with increasing light doses. The intratumor pH did not change significantly at these short times after PDT. In other R3327-AT and R3327-H tumor-bearing animals, [3H]misonidazole was administered 30 minutes prior to PDT treatments of both tumors. Twenty-four hours later, the tumors were resected in toto, and levels of retained [3H]misonidazole were determined in lased tumor specimens by liquid scintillation procedures. The amount of [3H]misonidazole activity in tumor tissue (covalently bound after hypoxic reduction) increased with light doses up to 3000 J. Sensitizer-adduct formation was found to correlate with the ratio of the concentration of inorganic phosphate to that of beta-ATP, both of which are presumed measures of tumor oxygenation status. These measurements have high-lighted the heterogenous nature of the oxygenation status of these experimental tumors. The precision of each assay for estimating tumor oxygenation is discussed.