Evaluation of hyperbaric oxygen as a chemosensitizer in the treatment of epithelial ovarian cancer in xenografts in mice

Abstract

Background. Resistance to chemotherapy is common in bulky hypoxic tumors such as epithelial ovarian cancer. Hyperbaric oxygen (HBO) oxygenates hypoxic tissues and promotes neovascularization. These unique properties of HBO may help overcome chemotherapy resistance by increasing both tumor perfusion and cellular sensitivity. This study was undertaken to determine if HBO increases the response of epithelial ovarian cancer to cisplatin chemotherapy. Methods. In Phase I, 64 nu/nu mice were divided into four groups and subcutaneously inoculated with cells from the A2780 human epithelial ovarian cancer cell line. Group 1 served as controls. Group 2 received weekly intraperitoneal cisplatin (3.15 mg/kg). Group 3 was exposed to HBO (dives) at 2.4 atmospheres absolute pressure for 90 minutes, 7 days a week. Group 4 received both cisplatin and HBO. In Phase II, 72 mice were divided into two groups and similarly inoculated. Both groups received weekly intraperitoneal cisplatin (2.5 mg/kg). Group 1 was not exposed to HBO. Group 2 was exposed to HBO for 5 days a week. Results. Dramatic tumor neovascularization was found in tumors of mice exposed to HBO P = 0.0001). There was significant (P = 0.014) tumor growth retardation in Phase I for mice receiving both cisplatin and HBO compared with those treated with cisplatin alone. This significance was noted after just two doses of cisplatin but subsequently lost due to reduced numbers of mice. In Phase II, neovascularization was detectable after 10 HBO treatments (2 weeks) and was maximal after 15 treatments (3 weeks). Conclusions. Hyperbaric oxygen increases vascularity in bulky tumors such as epithelial ovarian cancer There appears to be a relationship between increase vascularity and enhanced response to chemotherapy that merits further investigation.

Oxygenation inhibits ovarian tumor growth by down-regulating STAT3 and cyclin-D1 expressions

“…The relatively high levels of oxygen deliverable under HBO exposure make this approach attractive. Several studies in experimental animal tumors have shown that HBO reduces the radioresistance of certain types of tumors [6][7][8][9] and enhances the anticancer activity of doxorubicin and other alkylating agents. 10,11 Clinical trials have been initiated to study the effect of HBO inhalation on the radiotherapy for many types of malignant tumors.…”

Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

“…Because of this, HBO has previously been used to enhance the pO 2 in hypoxic tumor tissue, to potentiate the effect of radio- and photo-therapy in both clinical and preclinical trials and also the effect of some forms of chemotherapy like doxorubicin, alkylating agents and 5FU [13-16]. This effect has been ascribed as increased cytotoxicity of the tumor cells to the chemotherapeutic drug in vitro [16,17] and enhanced neovascularisation in vivo [18]. However, recent studies have shown reduced vascularisation after HBO treatment in vivo [19-21].…”

Pretreatment with Oxygen Protects Rat Kidney from Cisplatin Nephrotoxicity

“…[40] Daily HBO administration in mice not only does not reduce the therapeutic effect of weekly cisplatin on the bulky hypoxic tumors of epithelial ovarian cancer, but it also enhances the response to chemotherapy, which is likely due to increased tumoral vascularity. [41] Similarly, it has been determined that O(2/3) gas mixture has a direct anti-tumoral effect on human neuroblastoma cell lines, and that the combined O(2/3) and cisplatin treatment produces a stronger cell inhibitory effect compared to when cisplatin is used alone, which is attributed to the cell growth inhibition effect of oxygen therapy. [42] Nevertheless, it seems that the exact effect of oxygen pretreatment on therapeutic effects of chemotherapeutic agents has not been studied comprehensively and needs to be done.…”