Yaron J. Lidor

High-dose alkylating agent chemotherapy with autologous bone marrow support in patients with stage III/IV epithelial ovarian cancer☆

Although significant improvements in the treatment of ovarian cancer have been made over the past decade, the majority of patients with stage III and IV disease are still incurable with standard therapy. The median survival for patients who present with advanced disease is still less than 2 years. Paradoxically, ovarian cancer is very responsive to chemotherapy, with high overall response rates demonstrated consistently using cisplatinbased combination regimens [ 11. Surgically documented complete remissions are achieved in 40 to 60% of patients who begin chemotherapy with limited residual disease. However, with or without further therapy 37% [2] to 62% [3] of those complete responders will relapse and die of progressive tumor, leaving only 10 to 20% of advanced-stage patients disease free at 5 years. The single most common outcome for “good-prognosis” patients with surgically documented complete remissions or microscopic disease following induction chemotherapy is relapse of their ovarian cancer. It is this contrast of high response rates with major reductions in tumor burden, yet low numbers of durable complete remissions, that stimulated us to develop a dose-intensive multiagent chemotherapy regimen for advanced ovarian cancer. It seems clear that alternate methods of treatment are needed if increased numbers of cures are to be achieved.

In vitro expression of the diphtheria toxin A-chain gene under the control of human chorionic gonadotropin gene promoters as a means of directing toxicity to ovarian cancer cell lines ☆ ☆☆ ★ ★★

OBJECTIVE Our goal was to determine whether toxicity of the diphtheria toxin A-chain gene regulated by the human chorionic gonadotropin promoter can be directed to malignant ovarian cell lines. STUDY DESIGN Plasmids containing diphtheria toxin A-chain gene linked to the regulatory elements of the metalloergothioneine and human chorionic gonadotropin promoters were transfected into the cell lines. Expression of diphtheria toxin A-chain gene was determined by the inhibition of a cotransfected luciferase reporter gene. RESULTS Cytotoxicity of the diphtheria toxin A-chain gene is shown in a dose-responsive manner. Transfection of a plasmid expressing the diphtheria toxin A-chain gene controlled by a constitutive promoter readily inhibits protein synthesis. Specific inhibition of luciferase protein synthesis occurs in ovarian cancer cells transfected with the diphtheria toxin A-chain gene under the control of the human chorionic gonadotropin promoters when compared with normal ovarian epithelial cells or fibroblasts. CONCLUSIONS These data demonstrate the preferential expression of the diphtheria toxin A-chain gene, regulated by the human chorionic gonadotropin promoter, to ovarian cancer cell lines. This provides an avenue for targeting such cells for suicide, toxin, or cytokine genes.

Alkylating agents and immunotoxins exert synergistic cytotoxic activity against ovarian cancer cells. Mechanism of action.

Alkylating agents can be administered in high dosage to patients with ovarian cancer using autologous bone marrow support, but drug-resistant tumor cells can still persist. Immunotoxins provide reagents that might eliminate drug resistant cells. In the present study, concurrent treatment with alkylators and immunotoxins proved superior to treatment with each agent alone. Toxin immunoconjugates prepared from different monoclonal antibodies and recombinant ricin A chain (rRTA) inhibited clonogenic growth of ovarian cancer cell lines in limiting dilution assays. When alkylating agents and toxin conjugates were used in combination, the addition of the immunotoxins to cisplatin, or to cisplatin and thiotepa, produced synergistic cytotoxic activity against the OVCA 432 and OVCAR III cell lines. Studies performed to clarify the mechanism of action showed that cisplatin and thiotepa had no influence on internalization and binding of the 317G5-rRTA immunotoxin. Intracellular uptake of [195m]Pt-cisplatin was not affected by the immunoconjugate and thiotepa. The combination of the 317G5-rRTA and thiotepa, as well as 317G5-rRTA alone, increased [195m]Pt cisplatin-DNA adduct levels. The immunotoxin alone and in combination with the alkylators decreased intracellular glutathione levels and reduced glutathione-S-transferase activity. Repair of DNA damage induced by the combination of alkylators and 317G5-rRTA was significantly reduced when compared to repair after damage with alkylators alone. These findings suggest that immunotoxins affect levels and activity of enzymes required for the prevention and repair of alkylator damage.

High-dose alkylating agent chemotherapy with autologous bone marrow support in patients with stage III/IV epithelial ovarian cancer

Although significant improvements in the treatment of ovarian cancer have been made over the past decade, the majority of patients with stage III and IV disease are still incurable with standard therapy. The median survival for patients who present with advanced disease is still less than 2 years. Paradoxically, ovarian cancer is very responsive to chemotherapy, with high overall response rates demonstrated consistently using cisplatinbased combination regimens [ 11. Surgically documented complete remissions are achieved in 40 to 60% of patients who begin chemotherapy with limited residual disease. However, with or without further therapy 37% [2] to 62% [3] of those complete responders will relapse and die of progressive tumor, leaving only 10 to 20% of advanced-stage patients disease free at 5 years. The single most common outcome for “good-prognosis” patients with surgically documented complete remissions or microscopic disease following induction chemotherapy is relapse of their ovarian cancer. It is this contrast of high response rates with major reductions in tumor burden, yet low numbers of durable complete remissions, that stimulated us to develop a dose-intensive multiagent chemotherapy regimen for advanced ovarian cancer. It seems clear that alternate methods of treatment are needed if increased numbers of cures are to be achieved.