Correlation of Tumor Oxygen Dynamics with Radiation Response of the Dunning Prostate R3327-HI Tumor¹

Abstract

Our previous studies have shown that oxygen inhalation significantly reduces tumor hypoxia in the moderately well-differentiated HI subline of the Dunning prostate R3327 rat carcinoma. To test our hypothesis that modifying hypoxia could improve the radiosensitivity of these tumors, we performed experimental radiotherapy to compare the tumor response to ionizing radiation alone or in combination with oxygen inhalation. Tumor pO(2) measurements were performed on size-selected tumors several hours before radiotherapy using (19)F nuclear magnetic resonance echo planar imaging relaxometry (FREDOM) of the reporter molecule hexafluorobenzene. In common with our previous findings, the larger tumors (>3.5 cm(3)) exhibited greater hypoxia than the smaller tumors (<2 cm(3); P < 0.001), and oxygen inhalation reduced the hypoxic fraction (<10 Torr): In the larger tumors, hypoxic fraction dropped significantly from a mean baseline value of 80% to 17% (P < 0.001). The effect of oxygen administered 30 min before and during irradiation on tumor response to a single 30-Gy dose of photons was evaluated by growth delay. For the smaller tumors, no difference in growth delay was found when treatment was given with or without oxygen breathing. By contrast, breathing oxygen before and during irradiation significantly enhanced the growth delay in the larger tumors (additional 51 days). The differential behavior may be attributed to the low baseline hypoxic fraction (<10 Torr) in small tumors (20%) as a target for oxygen inhalation. There was a strong correlation between the estimated initial pO(2) value and the radiation-induced tumor growth delay (R > 0.8). Our histological studies showed a good match between the perfused vessels marked by Hoechst 33342 dye and the total vessels immunostained by anti-CD31 and indicated extensive perfusion in this tumor line. In summary, the present results suggest that the ability to detect modulation of tumor pO(2), in particular, the residual hypoxic fraction, with respect to an intervention, could have prognostic value for predicting the efficacy of radiotherapy.

VatuximabTM: Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

“…Results are also consistent with hypoxia estimates using the histological marker pimonidazole [212]. Most significantly, estimates of pO 2 and modulation of tumor hypoxia are found to be consistent with modified tumor response to irradiation [213,273]. Such prognostic capability could be important in the clinic, since it is known that relatively hypoxic tumors tend to be more aggressive and respond less well to radiation therapy [274][275][276].…”

“…7. We have used FREDOM to examine the effects of vascular targeting agents [36,267], vasoactive agents [215] and hyperoxic gases [10,200,[212][213][214][215][216][217][268][269][270]. We have shown that measurements are consistent with sequential determinations made using electrodes [271,272] and fiber optic probes (FOXY TM and OxyLite ) [201,216].…”

“…Many PFCs (e.g., PFTB, perflubron (often referred to as perfluorooctylbromide [PFOB]) and Therox TM (F44-E)) have several 19 F NMR resonances, which can be exploited to provide additional information in spectroscopic studies, but complicate effective imaging [209][210][211]. PFCs with a single resonance provide optimal signal-to-noise ratio (SNR) and simplify imaging: two agents hexafluorobenzene (HFB) [10,36,200,[212][213][214][215][216][217], and perfluoro-15-crown-5-ether (15C5) [218][219][220][221] have found extensive use. While most pO 2 investigations have exploited the R 1 sensitivity, R 2 is also sensitive as reported by Girard et al [222].…”

Molecular Imaging of Hypoxia

“…Moreover, relative hypoxia evaluated using pimonidazole and immunohistochemistry after tumor excision corresponded with baseline PO 2 observed by FREDOM before sacrifice (159). The FREDOM approach has been applied to diverse rodent tumors and human tumor xenografts in mice (129,152,(158)(159)(160). FREDOM has revealed distinct heterogeneity within and between tumors, both under baseline conditions and in response to interventions.…”

Local Radiation Therapy of B16 Melanoma Tumors Increases the Generation of Tumor Antigen-Specific Effector Cells That Traffic to the Tumor

“…Its efficacy, however, is limited by a number of parameters, including the oxygenation status of the tumor, the inherent radiation sensitivity of the tumor cells, and outgrowth of metastases at distant sites (7)(8)(9)(10). Importantly, tumor irradiation also elicits several immunomodulatory effects in vivo.…”