| Abstract | Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human cancers. Owing to their mode of action, DNA MGB-induced DNA damage may be a substrate for DNA MMR. This study was aimed at investigating the effect of loss of MMR on the sensitivity to brostallicin (PNU-166196), a novel synthetic alpha-bromoacrylic, second-generation DNA MGB currently in Phase II clinical trials and structurally related to distamycin A. Brostallicin activity was compared to a benzoyl mustard derivative of distamycin A (tallimustine). We report that the sensitivities of MLH1-deficient and -proficient HCT116 human colon carcinoma cells were comparable after treatment with brostallicin, while tallimustine resulted in a three times lower cytotoxicity in MLH1-deficient than in -proficient cells. MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart. In addition, p53-deficient mouse fibroblasts lacking PMS2 were as sensitive to brostallicin as PMS2-proficient cells, but were 1.6-fold resistant to tallimustine. Loss of neither ATM nor DNA-PK affected sensitivity to brostallicin in p53-deficient mouse embryonic fibroblasts, indicating that brostallicin-induced cytotoxicity in a p53-deficient genetic background does not seem to require these kinases. These data show that, unlike other DNA MGBs, MMR-deficient cells retain their sensitivity to this new alpha-bromoacrylic derivative, indicating that brostallicin-induced cytotoxicity does not depend on functional DNA MMR. Since DNA MMR deficiency is common in numerous types of tumours, brostallicin potentially offers the advantage of being effective against MMR-defective tumours that are refractory to several anticancer agents. |
| Authors | A Fedier, C Fowst, J Tursi, C Geroni, U Haller, S Marchini, D Fink
(Affiliation: Department of Obstetrics and Gynaecology, Division of Gynaecology, University Hospital of Zurich, CH-8091, Switzerland.)
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| Journal | British journal of cancer
(Br J Cancer)
Vol. 89
Issue 8
Pg. 1559-65
(Oct 20 2003)
ISSN: 0007-0920 England |
| PMID | 14562032
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Adaptor Proteins, Signal Transducing
- Antineoplastic Agents
- Carrier Proteins
- DNA-Binding Proteins
- Distamycins
- Guanidines
- MLH1 protein, human
- Mlh1 protein, mouse
- Neoplasm Proteins
- Nitrogen Mustard Compounds
- Nuclear Proteins
- Proto-Oncogene Proteins
- Pyrroles
- Tumor Suppressor Protein p53
- brostallicin
- tallimustine
- MSH2 protein, human
- Msh2 protein, mouse
- MutS Homolog 2 Protein
|
| Topics |
- Adaptor Proteins, Signal Transducing
- Adenocarcinoma
(pathology)
- Animals
- Antineoplastic Agents
(pharmacology)
- Base Pair Mismatch
- Carrier Proteins
- Cell Death
- Colonic Neoplasms
(pathology)
- DNA Repair
- DNA-Binding Proteins
- Distamycins
(pharmacology)
- Drug Resistance, Neoplasm
- Fibroblasts
- Guanidines
(pharmacology)
- Humans
- Mice
- MutS Homolog 2 Protein
- Neoplasm Proteins
(genetics)
- Nitrogen Mustard Compounds
(pharmacology)
- Nuclear Proteins
- Proto-Oncogene Proteins
- Pyrroles
(pharmacology)
- Tumor Cells, Cultured
- Tumor Suppressor Protein p53
|
