Brostallicin (PNU-166196)--a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells.
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.
Fedier
A
A
Department of Obstetrics and Gynaecology, Division of Gynaecology, University Hospital of Zurich, CH-8091, Switzerland.
Fowst
C
C
Tursi
J
J
Geroni
C
C
Haller
U
U
Marchini
S
S
Fink
D
D
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D016923:Cell Death; D003110:Colonic Neoplasms / Q000473:pathology*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004214:Distamycins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004214:Distamycins; D006146:Guanidines; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009588:Nitrogen Mustard Compounds; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; C066900:tallimustine; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; C455279:brostallicin