University of Louisville
Arsenic Alters the Expression of DNA Repair Proteins and Platinum Accumulation in Vivo After Murine Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Institution
University of Louisville
Faculty Advisor/ Mentor
J. Christopher States
Abstract
Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die with platinum-resistant disease. Adding hyperthermia to chemotherapy agents delivered intraperitoneally (HIPEC) may help to improve outcome. We developed a murine HIPEC model to test a combination of cisplatin (CP), sodium arsenite (NaAsO2) and hyperthermia (43°C). We established metastatic OC xenograft tumors in nude mice using CP-resistant human OC (A2780/CP70) cells. Tumorbearing mice were perfused for 1 h with 2 µM CP±40 µM NaAsO2 at 37 or 43°C. Cells expressing low levels of ERCC1, XPA and XPC, and high levels of MSH2 are known to be cisplatin sensitive. We analyzed expression of these proteins and p53 in tumors by Western blot. Both hyperthermia and arsenic, alone or in combination decreased CP-induced XPC levels 24 h after treatment. Arsenite blocked cisplatin suppression of MSH2. Our data indicate that arsenic is decreasing the levels of XPC and maintaining higher levels of MSH2, suggesting a mechanism of sensitization to cisplatin. Platinum and arsenic significantly accumulated in tumors during treatment (0 h). Platinum decreased by 24 h after treatment in the presence of arsenic. Systemic platinum accumulation during treatment with CP alone or the combination chemotherapy was in the order: kidney > liver = spleen > heart > brain. Tissue arsenic immediately after treatment was in the order: liver > kidney = spleen > heart > brain. Arsenic levels decreased significantly in all systemic tissues within 24h after treatment. Supported in part by NIH grants P30ES014443 and R01ES011314; and NSF-EPSCoR grant EPS-0447479.
Arsenic Alters the Expression of DNA Repair Proteins and Platinum Accumulation in Vivo After Murine Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die with platinum-resistant disease. Adding hyperthermia to chemotherapy agents delivered intraperitoneally (HIPEC) may help to improve outcome. We developed a murine HIPEC model to test a combination of cisplatin (CP), sodium arsenite (NaAsO2) and hyperthermia (43°C). We established metastatic OC xenograft tumors in nude mice using CP-resistant human OC (A2780/CP70) cells. Tumorbearing mice were perfused for 1 h with 2 µM CP±40 µM NaAsO2 at 37 or 43°C. Cells expressing low levels of ERCC1, XPA and XPC, and high levels of MSH2 are known to be cisplatin sensitive. We analyzed expression of these proteins and p53 in tumors by Western blot. Both hyperthermia and arsenic, alone or in combination decreased CP-induced XPC levels 24 h after treatment. Arsenite blocked cisplatin suppression of MSH2. Our data indicate that arsenic is decreasing the levels of XPC and maintaining higher levels of MSH2, suggesting a mechanism of sensitization to cisplatin. Platinum and arsenic significantly accumulated in tumors during treatment (0 h). Platinum decreased by 24 h after treatment in the presence of arsenic. Systemic platinum accumulation during treatment with CP alone or the combination chemotherapy was in the order: kidney > liver = spleen > heart > brain. Tissue arsenic immediately after treatment was in the order: liver > kidney = spleen > heart > brain. Arsenic levels decreased significantly in all systemic tissues within 24h after treatment. Supported in part by NIH grants P30ES014443 and R01ES011314; and NSF-EPSCoR grant EPS-0447479.