Biomaterial Database

Mechanisms of acquired resistance to the orally active platinum-based anticancer drug bis-acetato-ammine-dichloro-cyclohexylamine platinum (i.v.) (JM216) in two human ovarian carcinoma cell lines. 1994

K J Mellish, and L R Kelland

CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.

Acquired resistance to the p.o. active lipophilic platinum drug bis-acetato-ammine-dichloro-cyclohexylamine platinum (i.v.) (JM216) was generated in the 41M and CH1 human ovarian carcinoma cell lines, and their resistance mechanisms were compared to parallel cisplatin-resistant (cisR) cell lines. Intracellular platinum accumulation was not reduced in either 41M/JM216R or CH1/JM216R compared to the parent lines after JM216 exposure (1-100 microM for 2 h), and neither 41M/JM216R nor CH1/JM216R was cross-resistant to cadmium chloride, suggesting that metallothionein levels are not elevated. Resistance in 41M/JM216R (resistance factor, 1.9) appeared to be mainly due to elevated glutathione levels; levels were 1.6- and 1.8-fold higher in 41M/JM216R compared to 41M when expressed in terms of protein content and cell number respectively, reflected by a 1.7-fold reduction in total platinum bound to DNA in 41M/JM216R after JM216 exposure (10-100 microM for 2 h). This is in contrast to 41McisR, in which the major resistance mechanism was reduced intracellular accumulation. There was no difference between CH1 and CH1/JM216R in glutathione levels or levels of total platinum bound to DNA and DNA interstrand cross-links immediately after JM216 exposure (10-100 microM for 2 h or 25 microM for 2 h, respectively). In common with CH1cisR, increased DNA repair appeared to be the major resistance mechanism in CH1/JM216R (resistance factor, 6.2). Half times of removal of total platinum from DNA after JM216 exposure (25 microM for 2 h) were 20 h in CH1 and 11 h in CH1JM216R; at 24 h after JM216 exposure (25 microM for 2 h), no removal of DNA interstrand cross-links was observed in CH1, while in CH1/JM216R 20% of cross-links had been removed. These results suggest that compared to cisplatin, acquired resistance to JM216 is less likely to occur through reduced accumulation. However, resistance can result from elevated glutathione levels or increased DNA repair, mechanisms also shown to be involved in cisplatin resistance.

UI	MeSH Term	Description	Entries
D009944	Organoplatinum Compounds	Organic compounds which contain platinum as an integral part of the molecule.	Compounds, Organoplatinum
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
D010984	Platinum	A heavy, soft, whitish metal, resembling tin, with atomic number 78, atomic weight 195.084, symbol Pt. It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae".	Platinum Black
D004247	DNA	A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).	DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004260	DNA Repair	The removal of DNA LESIONS and/or restoration of intact DNA strands without BASE PAIR MISMATCHES, intrastrand or interstrand crosslinks, or discontinuities in the DNA sugar-phosphate backbones.	DNA Damage Response
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
D005260	Female		Females
D005978	Glutathione	A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides.	Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284	Administration, Oral	The giving of drugs, chemicals, or other substances by mouth.	Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations