P III A.8 Sensitivity to CCNU in methylation tolerant mismatch repair defective human cells

Aquilina, Gabriele; Ceccotti, Sabrina; Martinelli, Simone; Hampson, Richard; Bignami, Margherita

doi:10.1016/s0027-5107(97)82657-7

Cited by 6 publications

(15 citation statements)

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“…The selection of simultaneous mismatch repair and p53 defects in methylation tolerant cells was unprecedented in our experience. Methylation tolerant cells have been isolated from p53 positive or negative starting cells (Goldmacher et al, 1986;Branch et al, 1993;Aquilina et al, 1995) and tolerance is known to be una ected by the cell's p53 status (Aquilina et al, 1998;Hickman and Samson, 1999). This apparent anomaly was resolved by the demonstration of a subpopulation of A2780 cells which are both de®cient in hMLH1 expression and heterozygous for the p53phe172 mutation.…”

Section: Discussionmentioning

confidence: 99%

“…DU145 is derived from a prostatic carcinoma and is de®cient in both hMSH3 and hMLH1. DLD-1, SW48, LoVo and DU145 are all highly resistant to the methylating agent N-methyl-N-nitrosourea (Branch et al, 1995;Aquilina et al, 1998). In contrast, no systematic di erences in cisplatin resistance of repair pro®cient and de®cient cells were apparent (Figure 1).…”

Section: Tumor Cell Linesmentioning

confidence: 99%

“…The induced proteins control critical cellular functions including the levels of the p53 protein itself, progression through the cell cycle, and cellular apoptosis. Although methylating drugs can induce the p53 response, cell killing by these agents is independent of the cell's p53 status (Aquilina et al, 1998;d'Atri et al, 1998;Hickman and Samson, 1999). Cisplatin also induces the p53 response.…”

Section: Introductionmentioning

confidence: 99%

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Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Branch¹,

Masson²,

Aquilina

et al. 2000

Oncogene

102

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Section: Discussionmentioning

confidence: 99%

Section: Tumor Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Branch¹,

Masson²,

Aquilina

et al. 2000

Oncogene

102

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“…Loss of MMR is associated with resistance to TMZ, 6-thioguanine, cis-diaminedichloroplatinum(II) (CDDP), doxorubicin, and etoposide (for review, see Fink et al, 1998), and with hypersensitivity to CCNU (Aquilina et al, 1998). The MMR system, dedicated to the correction of biosynthetic errors (for review, see Modrich, 1997;Jiricny and Nyström-Lahti, 2000), involves the hMSH2, hMSH3, hMSH6, hMLH1, and hPMS2 polypeptides, as well as other proteins that participate in DNA metabolism (Modrich, 1997;Jiricny and Nyström-Lahti, 2000).…”

mentioning

confidence: 99%

“…In cells treated with CDDP, the MMR system may promote cell death by preventing recombinational repair of double-strand breaks that arise as secondary lesions of drug-induced DNA modifications (Karran, 2001). In contrast, in cells exposed to CCNU, it has been hypothesized that MMR participates in the removal of the interstrand cross-links generated by unrepaired O 6 -(2-chloroethyl)guanine, thus providing protection against cytotoxicity of the drug (Aquilina et al, 1998).…”

mentioning

confidence: 99%

The Effect ofO⁶-Alkylguanine-DNA Alkyltransferase and Mismatch Repair Activities on the Sensitivity of Human Melanoma Cells to Temozolomide, 1,3-bis(2-Chloroethyl)1-nitrosourea, and Cisplatin

Pepponi¹,

Marra²,

Fuggetta³

et al. 2003

J Pharmacol Exp Ther

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The prognosis of advanced melanoma is generally poor, because this tumor commonly exhibits intrinsic or acquired resistance to chemotherapy. In an attempt to identify the underlying causes of this resistance, we studied the roles played by the DNA repair enzyme O 6 -alkylguanine-DNA alkyltransferase (OGAT) and the mismatch repair (MMR) system in the sensitivity of melanoma cells to temozolomide (TMZ), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), or cis-diamminedichloroplatinum(II) (CDDP). To this end, OGAT levels and MMR efficiency of extracts of nine melanoma cell lines and selected clones derived from four of these lines were determined and correlated with the sensitivity of the respective cells to these drugs. The effectiveness of O 6 -benzylguanine (BG), a specific OGAT inhibitor, in potentiating TMZ-or BCNU-mediated cytotoxicity was also evaluated. Our results demonstrate that MMR efficiency and OGAT levels strongly affect melanoma cell sensitivity to TMZ. In MMR-proficient cells, a direct correlation between OGAT levels and TMZ IC 50 values was found. When OGAT activity was inhibited with BG, the sensitivity of these cells to TMZ increased and was then dictated largely by their MMR efficiency. MMR-deficient cells were highly resistant to the drug irrespective of their OGAT levels. Although OGAT activity and MMR status seemed to be the major determinants of melanoma sensitivity to TMZ, this was not the case for BCNU and CDDP; resistance to the latter drugs clearly involves processes other than the two DNA repair pathways analyzed in this study.

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Sensitivity to DNA cross-linking chemotherapeutic agents in mismatch repair-defective cellsin vitro and in xenografts

et al. 2000

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Together with tolerance to killing induced by methylating agents, loss of mismatch repair (MMR) has previously been found to be associated with hypersensitivity to the DNAcross‐linking agent 1‐(2‐chloroethyl)‐3‐cyclohexyl‐nitrosourea(CCNU) in several human tumor cell lines (Aquilina et al., 1998). Here, we have investigated whether MMR might act as an efficient repair pathway and provide protection against the clastogenicity induced by CCNU and whether the hypersensitivity of MMR‐defective cells is extended to other cross‐linking agents. An increase in cell killing and in the frequency of micronuclei was observed after CCNU exposure in 2 hPMS2‐defective clones (clones 6 and 7) compared with the parental HeLa cells. Introduction of a wild‐type copy of chromosome 7 in clone 7 led to re‐expression of the hPMS2 protein and brought survival and chromosomal damage upon CCNU exposure to parental levels. Our data indicate that MMR protects against the clastogenic damage induced by this drug. The hPMS2‐defective HeLa cells were also hypersensitive to killing by mitomycin C. Mitomycin C sensitivity was confirmed in an hMLH1‐defective clone derived from Raji cells and in msh2‐defective mouse embryo fibroblasts derived from knock‐out mice. hPMS2‐defective and parental HeLa cells were transplanted into nude mice, and the animals were treated with mitomycin C. While parental cell growth rate was unaffected, the growth of MMR‐defective tumor was significantly reduced. Our results indicate that the in vitro hypersensitivity to mitomycin C conferred by loss of MMR is paralleled in vivo and may have implications for the chemotherapy of MMR‐defective tumors. Int. J. Cancer 85:590–596, 2000. © 2000 Wiley‐Liss, Inc.

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P III A.8 Sensitivity to CCNU in methylation tolerant mismatch repair defective human cells

Cited by 6 publications

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Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

The Effect ofO⁶-Alkylguanine-DNA Alkyltransferase and Mismatch Repair Activities on the Sensitivity of Human Melanoma Cells to Temozolomide, 1,3-bis(2-Chloroethyl)1-nitrosourea, and Cisplatin

Sensitivity to DNA cross-linking chemotherapeutic agents in mismatch repair-defective cellsin vitro and in xenografts

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P III A.8 Sensitivity to CCNU in methylation tolerant mismatch repair defective human cells

Cited by 6 publications

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Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells

The Effect ofO6-Alkylguanine-DNA Alkyltransferase and Mismatch Repair Activities on the Sensitivity of Human Melanoma Cells to Temozolomide, 1,3-bis(2-Chloroethyl)1-nitrosourea, and Cisplatin

Sensitivity to DNA cross-linking chemotherapeutic agents in mismatch repair-defective cellsin vitro and in xenografts

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The Effect ofO⁶-Alkylguanine-DNA Alkyltransferase and Mismatch Repair Activities on the Sensitivity of Human Melanoma Cells to Temozolomide, 1,3-bis(2-Chloroethyl)1-nitrosourea, and Cisplatin