adozelesin and Uterine-Cervical-Neoplasms

U-73,975 (U-73), U-77,779 (U-77), and U-80,244 (U-80) are analogs of the potent antitumor compound CC-1065. This class of drugs act as alkylating agents binding to DNA preferentially. Using the ATP-chemosensitivity assay, this study was designed to compare the potencies of U-73, U-77, and U-80 with cisplatin (DDP) or adriamycin (DXR) in 10 gynecologic cancer cell lines. The mean IC50s were: U-73, 0.173 +/- 0.115 ng/ml; U-77, 0.650 +/- 0.209 ng/ml; U-80, 3.0 +/- 3.0 ng/ml; DDP, 4.40 +/- 2.83 micrograms/ml; and DXR, 0.286 +/- 0.040 micrograms/ml. U-73 appears the most potent analog, being 10(3) to 10(4) times more cytotoxic than DDP and DXR. U-77 and U-80 were somewhat comparable, demonstrating approximately 10(2) to 10(3) greater potency than DDP and DXR. All the cervical, endometrial, and ovarian cell lines were sensitive to U-73, with decreasing sensitivity to U-77, U-80, DXR, and DDP in that order. U-73 as well as the other analogs appear promising chemotherapeutic agents.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Benzofurans; Cisplatin; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Duocarmycins; Endometrial Neoplasms; Female; Humans; In Vitro Techniques; Indoles; Ovarian Neoplasms; Tumor Cells, Cultured; Urea; Uterine Cervical Neoplasms

U-73,975 (U-73), a closely related synthetic analogue of the antitumor agent CC-1065, acts by binding tightly in the minor groove of DNA. A comparison was made between the cytotoxicity of U-73 and cisplatin (DDP) on 11 fresh cervical and 7 fresh ovarian carcinoma specimens. The ATP-chemosensitivity assay as previously described (Sevin et al. Gynecol. Oncol. 31, 191-204, 1988) was used to determine the cytotoxic effect of U-73 and DDP. IC 50s were calculated using regression analysis. The mean IC 50s for U-73 and DDP were 519 pg/ml and 2918 ng/ml, respectively, for the cervical carcinoma specimens and 324 pg/ml and 2649 ng/ml, respectively, for the ovarian carcinoma specimens. Significance comparing U-73 and DDP for cervical and ovarian tissue was demonstrated with P < 0.001. U-73 was 4000 times as cytotoxic per unit of mass as DDP on cervical carcinoma compared to over 8000 times for ovarian carcinoma. Based on these in vitro data, U-73 appears to be a very promising antitumor agent for cervical and ovarian carcinoma.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Benzofurans; Cisplatin; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Duocarmycins; Female; Humans; In Vitro Techniques; Indoles; Ovarian Neoplasms; Regression Analysis; Uterine Cervical Neoplasms