Biomaterial Database

Overcoming cis-diamminedichloroplatinum (II) resistance of human ovarian tumor cells by combination treatment with cis-diamminedichloroplatinum (II) and tumor necrosis factor-alpha. 1993

Y Mizutani, and B Bonavida

Department of Microbiology and Immunology, UCLA School of Medicine 90024.

BACKGROUND Previous studies have demonstrated that tumor cells have different degrees of sensitivity and resistance to various cytotoxic agents. The acquisition of drug resistance is a major concern in cancer treatment. The current study investigates the cytotoxic effect of cis-diamminedichloroplatinum (II) (CDDP) and tumor necrosis factor-alpha (TNF-alpha) used in combination on CDDP-resistant human ovarian tumor cell lines. METHODS Cytotoxicity was determined by the microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. TNF-mRNA was examined by Northern blot analysis. RESULTS Treatment of the CDDP-resistant C30 cells with CDDP and TNF-alpha overcame the resistance of C30 cells to CDDP or TNF-alpha. In addition, the combination of CDDP and TNF-alpha resulted in a synergistic effect on the C30-resistant line, the CDDP-sensitive parental cell line A2780, and two freshly derived ovarian carcinoma cell cultures. Treatment of C30 cells with CDDP followed by TNF-alpha showed a synergistic effect, whereas treatment with TNF-alpha followed by CDDP demonstrated a less cytotoxic effect. A possible mechanism of resistance to TNF-alpha in tumor cells is the induction of TNF-alpha mRNA and protein. C30 cells do not produce mRNA constitutively for TNF-alpha; however, treatment of C30 cells with TNF-alpha induces the expression of TNF-alpha mRNA. When CDDP was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was reduced significantly. CONCLUSIONS This study shows that the combination of CDDP and TNF-alpha can overcome the CDDP resistance of tumor cells and that downregulation of TNF-alpha mRNA by CDDP may play a role in the enhanced cytotoxicity seen with the combination of CDDP and TNF-alpha. The synergistic effect obtained with established ovarian tumor cell lines and in short-term cultures of freshly isolated ovarian tumors suggests that combination treatment with TNF-alpha and CDDP may have clinical applications in the treatment of drug-resistant tumors.

UI	MeSH Term	Description	Entries
D010051	Ovarian Neoplasms	Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS.	Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D002945	Cisplatin	An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.	Platinum Diamminodichloride,cis-Diamminedichloroplatinum(II),cis-Dichlorodiammineplatinum(II),Biocisplatinum,Dichlorodiammineplatinum,NSC-119875,Platidiam,Platino,Platinol,cis-Diamminedichloroplatinum,cis-Platinum,Diamminodichloride, Platinum,cis Diamminedichloroplatinum,cis Platinum
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D004357	Drug Synergism	The action of a drug in promoting or enhancing the effectiveness of another drug.	Drug Potentiation,Drug Augmentation,Augmentation, Drug,Augmentations, Drug,Drug Augmentations,Drug Potentiations,Drug Synergisms,Potentiation, Drug,Potentiations, Drug,Synergism, Drug,Synergisms, Drug
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000971	Antineoplastic Combined Chemotherapy Protocols	The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.	Anticancer Drug Combinations,Antineoplastic Agents, Combined,Antineoplastic Chemotherapy Protocols,Antineoplastic Drug Combinations,Cancer Chemotherapy Protocols,Chemotherapy Protocols, Antineoplastic,Drug Combinations, Antineoplastic,Antineoplastic Combined Chemotherapy Regimens,Combined Antineoplastic Agents,Agent, Combined Antineoplastic,Agents, Combined Antineoplastic,Anticancer Drug Combination,Antineoplastic Agent, Combined,Antineoplastic Chemotherapy Protocol,Antineoplastic Drug Combination,Cancer Chemotherapy Protocol,Chemotherapy Protocol, Antineoplastic,Chemotherapy Protocol, Cancer,Chemotherapy Protocols, Cancer,Combinations, Antineoplastic Drug,Combined Antineoplastic Agent,Drug Combination, Anticancer,Drug Combination, Antineoplastic,Drug Combinations, Anticancer,Protocol, Antineoplastic Chemotherapy,Protocol, Cancer Chemotherapy,Protocols, Antineoplastic Chemotherapy,Protocols, Cancer Chemotherapy
D014407	Tumor Cells, Cultured	Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.	Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D014409	Tumor Necrosis Factor-alpha	Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.	Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D015536	Down-Regulation	A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.	Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor