The Opioid Growth Factor Inhibits Established Ovarian Cancer in Nude Mice and Can Be Combined with Taxol or Cisplatin to Enhance Growth Inhibition

摘要

Ovarian cancer is the 5th leading cause of cancer-related mortality in women. Seventy-five percent of ovarian cancer patients present in advanced stages, and receive cytoreductive surgery and adjuvant chemotherapy. However, within 2 years 65% of these patients relapse and thereafter only receive palliative care. Novel therapies based on the biology of these cancers are urgently needed. The opioid growth factor (OGF)-OGF receptor (OGFr) axis is an endogenous opioid system known to inhibit proliferation of human ovarian cancer cells in tissue culture, but does not affect cell survival. The present study determined whether OGF in combination with standard of care chemotherapy, provides an inhibitory effect on the growth of human ovarian cancer cells in vitro. In addition, this investigation assessed whether OGF biotherapy, alone or in combination with taxol or cisplatin, inhibits tumor growth in mice with xenografts of ovarian cancer. The combination of OGF (10–6 M) with taxol (10–9 M or 10–10 M) or cisplatin (0.01 ug/ml or 0.001 ug/ml) markedly reduced cell number and DNA synthesis in vitro to a greater extent than individual compounds. OGF, but not taxol or cisplatin, altered growth in an opioid receptor mediated and reversible manner. Female nuu mice inoculated subcutaneously with SKOV-3 cells, and treated with OGF (10 mg/kg) for 5 weeks commencing at the time tumors became measurable, had tumor volumes and weight that were reduced by up to 50% from animals receiving saline. The combination of OGF with taxol (3 mg/kg, weekly) or cisplatin (4 mg/kg, weekly for 2 weeks) for 37 days reduced tumor volumes and weight in contrast to mice receiving individual agents alone. Moreover, OGF treatment in mice receiving cisplatin provided protection against the weight loss associated with cisplatin alone. All treatments suppressed DNA synthesis and angiogenesis, whereas exposure to taxol or cisplatin, but not OGF, induced apoptosis. Additive inhibitory effects on DNA synthesis and angiogenesis were recorded in animals treated with both OGF and taxol, or OGF and cisplatin, in comparison to individual compounds alone. OGF and OGFr were detected in tumor tissue; however OGFr expression was reduced 51% - 81% by OGF treatment. This preclinical evidence demonstrates that OGF biotherapy markedly inhibits ovarian tumorigenesis in a non-toxic manner, and can be combined with taxol or cisplatin to provide an enhanced therapeutic benefit.