caa a22 4500 397565410 CHVBK 20180308164827.0 cr unu---uuuuu 161202e19960605xx s 000 0 eng 10.1093/jnci/88.11.734 doi (NATIONALLICENCE)oxford-10.1093/jnci/88.11.734 Cytotoxic Effects of Topotecan Combined With Various Anticancer Agents in Human Cancer Cell Lines [Elektronische Daten] [Scott H. Kaufmann, David Peereboom, Christopher A. Buckwalter, Phyllis A. Svingen, Louise B. Grochow, Ross C. Donehower, Eric K. Rowinsky] Background: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. Purpose: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. Methods: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincris-tine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chlo-roethyl]nitrosourea [BCNU], or 4-hy-droperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82rasH lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). Results: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at ≥90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82rasH cells, synergy was observed over most of the cytotoxicity range. Conclusions and Implications: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or anti-microtubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo. © Oxford University Press REPORTS nationallicence Kaufmann Scott H. Division of Oncology Research, Mayo Clinic Rochester, MN aut Peereboom David Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut Buckwalter Christopher A. Division of Oncology Research, Mayo Clinic Rochester, MN aut Svingen Phyllis A. Division of Oncology Research, Mayo Clinic Rochester, MN aut Grochow Louise B. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut Donehower Ross C. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut Rowinsky Eric K. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut JNCI: Journal of the National Cancer Institute Oxford University Press 88/11(1996-06-05), 734-741 0027-8874 88:11<734 1996 88 jnci https://doi.org/10.1093/jnci/88.11.734 text/html Onlinezugriff via DOI 1 other jats NATIONALLICENCE 856 40 https://doi.org/10.1093/jnci/88.11.734 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kaufmann Scott H. Division of Oncology Research, Mayo Clinic Rochester, MN aut NATIONALLICENCE 700 1- Peereboom David Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut NATIONALLICENCE 700 1- Buckwalter Christopher A. Division of Oncology Research, Mayo Clinic Rochester, MN aut NATIONALLICENCE 700 1- Svingen Phyllis A. Division of Oncology Research, Mayo Clinic Rochester, MN aut NATIONALLICENCE 700 1- Grochow Louise B. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut NATIONALLICENCE 700 1- Donehower Ross C. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut NATIONALLICENCE 700 1- Rowinsky Eric K. Division of Pharmacology and Experimental Therapeutics, Johns Hopkins Oncology Center Baltimore, MD aut NATIONALLICENCE 773 0- JNCI: Journal of the National Cancer Institute Oxford University Press 88/11(1996-06-05), 734-741 0027-8874 88:11<734 1996 88 jnci Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford