Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells.

We have examined microsatellite instability and loss of p53 function in human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independent cisplatin-resistant sublines are RER(+), whereas the parental line shows no evidence of microsatellite instability. Microsatellite mutations in random, nonselected subclones of a cislatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently induced by DNA damage. Furthermore, a cisplatin-resistant derivative shows reduction in a G:T mismatch recognition activity compared to the parental line. Independent lines selected by multiple exposure to cisplatin show resistance factors of up to a 5-fold by clonogenic assay and have reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured by a loss of radiation-induced G(1) arrest and reduced CIP1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduced ability to engage apoptosis and loss of p53 function.

[1]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[2]  J C Reed,et al.  The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. , 1995, Oncogene.

[3]  K. Kinzler,et al.  Mismatch repair deficiency in phenotypically normal human cells , 1995, Science.

[4]  A. Bowcock,et al.  Genetic instability in human ovarian cancer cell lines. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Brown,et al.  Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity. , 1994, Cancer research.

[6]  W. Kaufmann,et al.  Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. , 1994, Cancer research.

[7]  Y. Nakamura,et al.  Frequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers. , 1994, Cancer Research.

[8]  A. Składanowski,et al.  Relevance of interstrand DNA crosslinking induced by anthracyclines for their biological activity. , 1994, Biochemical pharmacology.

[9]  John Calvin Reed,et al.  Identification of a p53-dependent negative response element in the bcl-2 gene. , 1994, Cancer research.

[10]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[11]  D. Ward,et al.  Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer , 1994, Nature.

[12]  M. Tilby,et al.  Differential sensitivity to the induction of apoptosis by cisplatin in proliferating and quiescent immature rat thymocytes is independent of the levels of drug accumulation and DNA adduct formation. , 1994, Cancer research.

[13]  Bert Vogelstein,et al.  Hypermutability and mismatch repair deficiency in RER+ tumor cells , 1993, Cell.

[14]  P. Karran,et al.  Incision at DNA G.T mispairs by extracts of mammalian cells occurs preferentially at cytosine methylation sites and is not targeted by a separate G.T binding reaction. , 1993, Biochemistry.

[15]  R. Ozols,et al.  Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines. , 1993, Cancer research.

[16]  D. Housman,et al.  p53-dependent apoptosis modulates the cytotoxicity of anticancer agents , 1993, Cell.

[17]  J. Hickman,et al.  Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. , 1993, The EMBO journal.

[18]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[19]  B. Gallie,et al.  Mutations of the p53 gene do not occur in testis cancer. , 1993, Cancer research.

[20]  W. Thilly,et al.  An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[22]  G. Aquilina,et al.  Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage , 1993, Nature.

[23]  Thea D. Tlsty,et al.  Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53 , 1992, Cell.

[24]  M. Kastan,et al.  Wild-type p53 is a cell cycle checkpoint determinant following irradiation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Bartek,et al.  An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. , 1992, Journal of immunological methods.

[26]  J. Hays,et al.  Recombinagenic processing of UV-light photoproducts in nonreplicating phage DNA by the Escherichia coli methyl-directed mismatch repair system. , 1991, Genetics.

[27]  J. Mattick,et al.  'Touchdown' PCR to circumvent spurious priming during gene amplification. , 1991, Nucleic acids research.

[28]  K. McLaughlin,et al.  Single step selection of cis-diamminedichloroplatinum(II) resistant mutants from a human ovarian carcinoma cell line. , 1991, Cancer research.

[29]  A. Eastman,et al.  Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. , 1991, The Journal of clinical investigation.

[30]  R. Epstein,et al.  Drug-induced DNA damage and tumor chemosensitivity. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  S. Lippard,et al.  Effect of the antitumor drug cis-diamminedichloroplatinum(II) and related platinum complexes on eukaryotic DNA replication. , 1990, Biochemistry.

[32]  P. Walker,et al.  Periodicity of DNA folding in higher order chromatin structures. , 1990, The EMBO journal.

[33]  A. Pa,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990 .

[34]  S. Howell,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990, Cancer cells.

[35]  J. Jiricny,et al.  A human 200-kDa protein binds selectively to DNA fragments containing G.T mismatches. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Kaye,et al.  The multidrug resistance phenotype. , 1988, British Journal of Cancer.

[37]  S. Lippard,et al.  Structural aspects of platinum anticancer drug interactions with DNA , 1987 .

[38]  R C Young,et al.  Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. , 1987, Cancer research.

[39]  A. Tulpule,et al.  Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T. Kao,et al.  Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. , 1985, Nucleic acids research.

[41]  R. Ozols,et al.  Reversal of adriamycin resistance by verapamil in human ovarian cancer. , 1984, Science.

[42]  S K Carter,et al.  Adriamycin. A new anticancer drug with significant clinical activity. , 1974, Annals of internal medicine.