Murine leukemia L1210 cell lines with different patterns of resistance to platinum coordination complexes.
ABSTRACT A murine leukemia L1210 cell line has been developed that exhibits 30-fold resistance to 1,2-diaminocyclohexaneplatinum(II) analogs but retains sensitivity to cisplatin. This contrasts existing cell lines which exhibit the opposite pattern of resistance. Both cell lines retain their sensitivity to melphalan.
Article: Multiple mechanisms of resistance to cis-diamminedichloroplatinum(II) in murine leukemia L1210 cells.[show abstract] [hide abstract]
ABSTRACT: As an experimental model for resistance to cis-diamminedichloroplatinum(II) (cis-DDP), murine leukemia L1210 cells have been exposed to a stepwise increase in cis-DDP concentration to produce a variety of resistant cell lines. Intraspecies hybrids of the sensitive and resistant cells were made to determine whether cis-DDP resistance is a dominant or recessive trait. Hybrid cells displayed a partial degree of resistance as compared to the parental cells. To determine whether this was due to a single codominant trait or contribution from a variety of resistance mechanisms, the cells and hybrids were investigated for alterations in the accumulation of drug, as well as alterations in glutathione levels which might inactivate the drug. The cis-DDP-resistant cells demonstrated both a 50% reduction in accumulation of drug and a 1.7-fold increase in intracellular glutathione. Reducing the glutathione levels in these cells with buthionine sulfoximine did not sensitize them to cis-DDP. The hybrid cells had the same accumulation and the same levels of glutathione as the cis-DDP-sensitive cells. Parallel studies were performed with cells resistant to 1,2-diaminocyclohexaneplatinum(II) analogues. These cells also demonstrated reduced drug accumulation but no increase in glutathione. Therefore, both a decrease in accumulation and increase in glutathione may mediate resistance. Both mechanisms represent recessive traits as demonstrated in the cell hybrids. These mechanisms can only account for a small part of the resistance in these cells. A major, dominant mechanism occurs after the DNA has been platinated, but it remains to be determined whether this involves DNA repair, postreplication repair, or some other as yet unidentified process.Cancer Research 05/1987; 47(8):2056-61. · 7.86 Impact Factor
Article: Increased gene specific repair of cisplatin induced interstrand crosslinks in cisplatin resistant cell lines, and studies on carrier ligand specificity.[show abstract] [hide abstract]
ABSTRACT: Development of resistance to cisplatin in previously treatment-responsive malignancies is a major obstacle to successful treatment. Enhanced DNA repair as well as enhanced replicative bypass of DNA adducts have been suggested to play a role in the development of resistance to cisplatin. However, the relative contribution of these mechanisms is unknown. Second generation platinum compounds containing the 1,2-diaminocyclohexane (dach) carrier ligand have been of particular interest in the studies of resistance mechanisms since they have been effective in treatment of cells resistant to cisplatin. We have investigated the formation and repair of interstrand crosslinks (ICL) in the mouse leukemia cell line L1210/0 and its carrier ligand specific resistant derivatives L1210/DDP and L1210/DACH after treatment with ethylenediamine (en)-Pt and diaminocyclohexane (dach)-Pt compounds. ICL in the overall genome were examined using a modification of the alkaline elution assay. A Southern blot technique was employed for the study of ICL in specific regions of the genome. In the overall genome we found decreased formation of ICL with either -en or -dach carrier ligands in the two resistant cell lines without carrier ligand specificity. Some carrier ligand specificity of ICL formation was observed in the dihydrofolate reductase (DHFR) gene, but it did not correlate with the carrier ligand specificity of resistance. At the level of the overall genome there was no difference in repair of ICL between the sensitive and the two resistant cell lines. When measured in the DHFR gene, however, there was enhanced repair of ICL in the two resistant cell lines compared with the sensitive cell line. The enhanced repair at the level of the gene did not display any carrier ligand specificity.Carcinogenesis 01/1997; 17(12):2597-602. · 5.70 Impact Factor
Article: Differential uptake of cis-diamminedichloroplatinum (II) by sensitive and resistant murine L1210 leukemia cells.[show abstract] [hide abstract]
ABSTRACT: The uptake of cis-[14C]dichloro(ethylenediamine)platinum(II) (cis-DEP) is reduced in cis-diamminedichloroplatinum(II) (cis-DDP)-resistant L1210 cells [L1210/DDP (SRI)] in comparison to cis-DDP-sensitive L1210 cells (L1210/0). A difference in uptake is observed as early as 6 min after addition of cis-[14C]DEP and increases to approximately 3-fold after 30 min. This reduction in uptake is reflected in a decrease in the binding of platinum to DNA isolated from cis-DDP-treated cells as measured by atomic absorption spectroscopy and in the quantity of intracellular cis-DEP metabolites as measured by high-performance liquid chromatography. Similar differences in uptake are observed between ascitic L1210/0 and L1210/DDP (SRI) cells in vitro and in vivo, showing that the differences in uptake are not due to an artifact of the culturing process. The differences in cis-DEP uptake between the two cell lines were relatively unchanged during 7 mo in culture; however, both cell lines exhibited altered sensitivities to cis-DEP during extended culturing. No difference was observed in the efflux of cis-DEP by the two cell lines. Similarly, no difference in nonprotein and total sulfhydryl contents was observed between L1210/0 and L1210/DDP (SRI) cells. The difference in uptake (3-fold) of cis-DEP between L1210/0 and L1210/DDP (SRI) cells may not account fully for the observed differences in sensitivity of the two cell lines to cis-DDP (18-fold) and cis-DEP (19-fold). A portion of the resistance may be due to differences in the capacity of the two cell lines to survive in the presence of platinum damage.Cancer Research 01/1988; 47(24 Pt 1):6549-55. · 7.86 Impact Factor