Binding activities of <i>cis</i>‐platin‐damage‐recognition proteins in human tumour cell lines

McLaughlin, Karen; Coren, Grant; Masters, J. R. W.; Brown, Robert E.

doi:10.1002/ijc.2910530423

Cited by 14 publications

(5 citation statements)

References 24 publications

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“…However, other parameters that we did not include in this study (for review see Kelland, 1994) might explain the sensitivity of germ cell tumour and the insensitivity of colon carcinoma cell lines. Thus the sensitivity of germ cell tumours to a range of drugs inducing DNA damage and the possible role of DNA damage recognition proteins (McLaughlin et al, 1993) are intriguing.…”

Section: Methodsmentioning

confidence: 99%

Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Sark

Timmer‐Bosscha²,

Meijer³

et al. 1995

Br J Cancer

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Cisplatin (CDDP) resistance mechanisms were studied in a model of three germ cell tumour and three colon carcinoma cell lines representing intrinsically CDDP-sensitive and -resistant tumours respectively. The CDDP sensitivity of the cell lines mimicked the clinical situation. The glutathione levels of the cell lines correlated with CDDP concentrations inhibiting cell survival by 50% (IC50); total cellular sulphydryl content (TSH) was unexpectedly inversely correlated with IC50. IC50 correlated neither with glutathione S-transferase (GST) nor with GST pi expression, topoisomerase I or II activity. Immediately after 4 h incubation with CDDP, platinum (Pt) accumulation and Pt bound to DNA were not correlated, but after another 24 h drug-free culture, Pt binding to DNA in germ cell tumour but not in colon carcinoma cell lines correlated with IC50. With the exception of in vitro sensitivity and TSH, none of the parameters studied discriminated between the two groups of cell lines. Correction of CDDP sensitivity parameters for phenotypical differences did not influence statistical correlations. Analysis of variance revealed a correlation between IC50 and the combination of glutathione, GST activity and Pt bound to DNA. But at other CDDP cytotoxicity levels sensitivity was also correlated with Pt accumulation, topoisomerase II activity and TSH in various combinations. This model of intrinsic CDDP resistance showed that multiple parameters ought to be studied to explain CDDP resistance, but did not elucidate the cause of the unique sensitivity of germ cell carcinoma, although the unexpected values of TSH deserve further attention.

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Section: Methodsmentioning

confidence: 99%

Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Sark

Timmer‐Bosscha²,

Meijer³

et al. 1995

Br J Cancer

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“…There is evidence that increased expression of damage recognition proteins may correlate with CDDP resistance (CHu & Chang, 1990;Chao et al, 1991c;McLaughlin et al, 1992). This paper describes the identification of CDDPdamage recognition proteins in cell extracts from human tumour cell lines and tumour biopsies using gel-mobility shift and southwestern blot assays.…”

mentioning

confidence: 99%

Cisplatin-DNA damage recognition proteins in human tumour extracts

Bissett¹,

McLaughlin²,

Kèlland³

et al. 1993

Br J Cancer

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“…Enhanced cisplatin emux and increased GSli lcvels could account, at least in part, for the lower concentration of platinum bound to DNA. Higher levels of cisplatin-damagerecognition proteins have been reported in cisplatin-resistant IGR-OV1 cells selected by intermittent exposure to drug, which could reflect enhanced DNA repair (McLaughlin et al, 1993). Whether or not thcsc proteins are over-expressed in IGR-OVl /DDP cells exposed continuously to cisplatin remains to be determined.…”

Section: Figure 8 -Mdm-2 Immunocytochemical Analysis Of Igr-ov1mentioning

confidence: 98%

Cisplatin-induced apoptosis andp53 gene status in a cisplatin-resistant human ovarian carcinoma cell line

et al. 1996

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Cisplatin-induced apoptosis and pS3 gene status were analyzed in human ovarian carcinoma usin a parental IGR-OVI line and a derived cisplatin-resistant I&-OVI /DDP subline. Compared with parental cells, cisplatin-resistant cells exhibited a 5-fold higher resistance index and a 2-fold longer doubling time. Cisplatin induced apoptosis in both cell lines, as assessed by cell morphology and the presence of a DNA ladder. However, high concentrations were necessary to induce apoptosis in resistant cells. These cells elicited a 5-fold decrease in the number of platinum atoms bound per nucleotide. IGR-OVI/ DDP cells also exhibited enhanced drug efflux and a higher glutathione content. Our data suggest that the levels of cisplatin-DNA lesions are critical for drug sensitivity and apoptosis induction in this in vitro ovarian carcinoma model. Comparative analysis of the pS3 gene in sensitive and resistant cells revealed the presence of the same heterozygous mutation in exon 5. A 2-fold increase in pS3 mRNA and protein amounts was observed in resistant cells as assessed by Northern and Western blots, respectively. lmmuncqtochemical staining revealed a higher percentage of p53 stained nuclei in resistant cells. RT-PCR analysis of pS3 transcripts showed that both wild-type and mutated alleles were transcribed in sensitive as well as in resistant cells. However, mutated transcripts were I .5-fold more abundant than wild-type transcripts in sensitive cells, whereas they were 2-fold higher in resistant cells. In addition, mdm-2 protein was over-expressed in resistant cells. Our results address the question of the functionality of p53 protein and its possible role in apoptosis induction in this model. In resistant cells, p53 protein might be inactivated by 2 mechanisms: mutation and complexation with mdm-2 protein. Therefore, the presence of non-functional p53 in resistant cells might be involved in the relative failure of cisplatin-induced apoptosis in these cells.o 1996 Wiley-Liss, Inc.Platinum-based chemotherapy is a standard treatment for ovarian canccr. Howevcr, the initial positive responses to therapy are often limited by thc development of drug rcsistance. Resistance to anti-tumor treatments may be due to impaired drug availability, altered host metabolism or the induction or selection of resistant cells. DNA is the critical intracellular target for platinum compounds, and cytotoxicity is thought to be mediatcd by thc inhibition of DNA synthesis after formation of platinum-DNA cross-links. Various mcchanisms responsiblc for the development of cellular resistance to platinum complexes have bcen reported and include altered membrane transport, inactivation of the drug by cellular thiols such as glutathione as well as mctallothioneins and incrcascd tolerance of DNA damage o r incrcascd repair (Andrews and Howell, 1990).However, there is cvidence that drug-target interaction is not the sole determinant of cellular sensitivity to chemothcrapcutic agents. Although they intcract with different targets, most of the cytotoxic ant...

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Binding activities of cis‐platin‐damage‐recognition proteins in human tumour cell lines

Cited by 14 publications

References 24 publications

Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines

Cisplatin-DNA damage recognition proteins in human tumour extracts

Cisplatin-induced apoptosis andp53 gene status in a cisplatin-resistant human ovarian carcinoma cell line

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