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. Ho...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 nu/nu 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.展开更多
The opioid growth factor (OGF) and its receptor (OGFr) regulate human ovarian cancer cell proliferation through a tonically active inhibitory axis. We investigated the effect of OGFr overexpression on ovarian tumorige...The opioid growth factor (OGF) and its receptor (OGFr) regulate human ovarian cancer cell proliferation through a tonically active inhibitory axis. We investigated the effect of OGFr overexpression on ovarian tumorigenesis. Clonal cell lines of SKOV-3 human ovarian cancer were established to stably overexpress OGFr. shRNA constructs were evaluated for antitumor activity in vitro, as well as in vivo using mouse models of s.c. and i.p. tumor transplantation. The 5 clonal cell lines were characterized by increases in OGFr protein (62% to 245%) and binding capacity (51% - 154%), and decreases (36% - 185%) in cell number, relative to untransfected wild-type (WT) cells and empty vector (EV) transfected clones. Nude mice receiving s.c. injection of 2 overexpressing OGFr cell lines (OGFr-3 and OGFr-22) had reduced tumor incidence, delayed tumor appearance (up to 12 days), and decreased tumor volume (up to 87%) relative to WT and EV controls. Mice injected i.p. with these clonal lines displayed reduced formation of tumor nodules (up to 95%), and depressed tumor weights (up to 99%) compared to WT and EV groups. DNA synthesis, but not cell survival, was depressed in cells and s.c. tumors overexpressing OGFr in comparison to the WT and EV groups. Angiogenesis was reduced up to 86% in clonal tumors compared to WT and EV groups. This preclinical evidence demonstrates that OGFr expression is a molecular determinant of ovarian cancer progression, and has important relevance to understanding the pathogenesis and treatment of this deadly disease.展开更多
文摘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 nu/nu 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.
文摘The opioid growth factor (OGF) and its receptor (OGFr) regulate human ovarian cancer cell proliferation through a tonically active inhibitory axis. We investigated the effect of OGFr overexpression on ovarian tumorigenesis. Clonal cell lines of SKOV-3 human ovarian cancer were established to stably overexpress OGFr. shRNA constructs were evaluated for antitumor activity in vitro, as well as in vivo using mouse models of s.c. and i.p. tumor transplantation. The 5 clonal cell lines were characterized by increases in OGFr protein (62% to 245%) and binding capacity (51% - 154%), and decreases (36% - 185%) in cell number, relative to untransfected wild-type (WT) cells and empty vector (EV) transfected clones. Nude mice receiving s.c. injection of 2 overexpressing OGFr cell lines (OGFr-3 and OGFr-22) had reduced tumor incidence, delayed tumor appearance (up to 12 days), and decreased tumor volume (up to 87%) relative to WT and EV controls. Mice injected i.p. with these clonal lines displayed reduced formation of tumor nodules (up to 95%), and depressed tumor weights (up to 99%) compared to WT and EV groups. DNA synthesis, but not cell survival, was depressed in cells and s.c. tumors overexpressing OGFr in comparison to the WT and EV groups. Angiogenesis was reduced up to 86% in clonal tumors compared to WT and EV groups. This preclinical evidence demonstrates that OGFr expression is a molecular determinant of ovarian cancer progression, and has important relevance to understanding the pathogenesis and treatment of this deadly disease.
