HYPEROXIC RESPIRATORY CHALLENGES TO MONITOR CHEMOTHERAPY EFFECTS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background: Response to cancer treatments such as radiotherapy, chemotherapy, and photodynamic therapy are less effective when tumors are hypoxic. Hyperoxic gas intervention has been shown to improve tumor oxygenation. Here we report how hemodynamic changes due to oxygen intervention are related to the tumor response during cisplatin treatment of spontaneous mammary tumors developed in mice with conditional inactivation of the Brca1 and p53 genes. Materials and Methods: We treated mammary tumors in Brca1/p53 knockout mice (n=8) with 1.2mg/kg of Cisplatin (i. p. daily for a week), and tumor volume and body weight were monitored during treatment. We imaged tumors during chemotherapy using an optical imaging system that quantifies intrinsic light scattering and absorption by projecting spatially modulated, near infrared (NIR) light (650nm to 980nm) onto tissues and calculating oxy-(OHb), deoxy-(RHb), total hemoglobin (THb) concentrations, tissue oxygen saturation (StO2) values, and scattering values at all wavelengths. During imaging, animals were anesthetized using 1.5% isoflurane and each animal inhaled medical air (33% O2) for 6 min followed by 100% oxygen for an additional 12 min. Results: Among 8 tumors, 5 (volume=0.38¿0.1) showed response to Cisplatin treatment while the other 3 tumors (volume=0.56¿0.12) did not. Tumors responding to Cisplatin displayed greater than 2-fold increase in [OHb] and [RHb] during oxygen intervention compared to non responding tumors (p<0.05). (Fig.1) Significant differences in tumor size changes (data not shown) were also observed between responders and non-responders. Discussion: Breast cancers are heterogeneous in their molecular profiles as well as treatment response. Hyperoxic gas intervention during chemotherapy combined with intrinsic signal optical imaging can be used to evaluate vascular reactivity. Our preliminary results indicate that OHb and RHb reactive tumors are significantly more likely to respond to Cisplatin chemotherapy. This general approach can be extended to other tumor therapy models and can be readily translated to patients.