PubMed · 11686014
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Y Nieto, R B Jones. 2001. DNA-binding agents.. https://pubmed.ncbi.nlm.nih.gov/11686014/
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The objective of this study was to further define the role of homologous recombinational repair (HRR) in resistance to the nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). We have demonstrated previously that increased chlorambucil (CLB)-induced HsRad51 nuclear foci formation correlated with a CLB-resistant phenotype in B-CLL lymphocytes. In this report, we measured the protein levels of HsRad51 and Xrcc3 (an HsRad51 paralog) and correlated them with the in vitro CLB cytotoxicity (LD(50)) in lymphocytes from seventeen B-CLL patients. Both HsRad51 (r=0.75, P=0.0005) and Xrcc3 (r=0.52, P=0.03) protein levels correlated with the in vitro CLB LD(50). In addition, multiple linear regression analysis showed a significant correlation between Xrcc3 and Rad51 protein levels versus the CLB LD(50) (r=0.78, P=0.0014), suggesting that both proteins influence CLB cytotoxicity. Moreover, since HsRad51 expression varies in cell lines during the cell cycle, we determined proliferating cell nuclear antigen (PCNA) protein levels to assess possible differences in cell cycle progression. There was no correlation between PCNA protein levels and the CLB LD(50) (r=0.042, P=0.87) or with HsRad51/Xrcc3 protein levels. Our data suggest that HsRad51 and Xrcc3 protein expression may be predictive of the response in B-CLL patients to treatment with nitrogen mustards.
Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type can regress after anti-Helicobacter pylori treatment. The International Extranodal Lymphoma Study Group, the United Kingdom Lymphoma Group, and the Groupe d'Etude des Lymphomes de l'Adulte have conducted a trial to ascertain whether the addition of chlorambucil is of benefit after anti-H pylori therapy. At the last interim analysis, 105 (55%) of 189 patients had achieved a complete histologic remission after anti-Helicobacter therapy. To further assess the ability of treatment to eradicate the lymphoma clone, we analyzed the gastric biopsies from a subset of the patients by polymerase chain reaction (PCR) targeted to the immunoglobulin heavy chain genes as a molecular marker for minimal residual disease. Sixty-two cases were examined at diagnosis. Fifty-four cases were monoclonal by PCR. Forty-two of these patients achieved histologic complete remission (hCR) after anti-Helicobacter treatment: 34 cases underwent molecular follow-up analysis. Fifteen patients (44%) were in molecular remission with a median follow-up of 2 years after antibiotic treatment and of 1 year after the achievement of hCR. Less than half of the patients with MALT lymphoma can achieve sustained molecular remission after anti-Helicobacter therapy. The presence of molecular disease in the absence of histologic disease does not appear to be associated with histologic relapse, but, given the indolent nature of MALT lymphomas, a longer follow-up is needed.
p53 is an important player in the cellular response to genotoxic stress whose functions are regulated by phosphorylation of a number of serine and threonine residues. Phosphorylation of p53 influences its DNA-binding and gene regulation activities. This study examines p53 phosphorylation in HCT-116 (MMR-deficient) and HCT-116+ch3 (MMR-proficient) human colon cancer cells treated with a S(N)2 DNA-alkylating agent, methylmethane sulfonate (MMS). MMS induces phosphorylation of p53 on Ser15 and Ser392 in a dose- and time-dependent manner. MMS-induced p53 phosphorylation is independent of DNA mismatch repair (MMR) activity. Nuclear extracts from MMS-treated HCT-116 cells had higher p21WAF1/Cip1 (p21) promoter DNA-binding activity in vitro opposed to untreated cells. After MMS treatment, the activation of the cloned p21 promoter in a transient transfection assay and endogenous p21 mRNA levels in HCT-116(p53+/+) versus HCT-116(p53-/-) cells increased, which correlates with an increased levels of phospho-p53(Ser15) and phospho-p53(Ser392). These results suggest that SN2 DNA-alkylating agent-induced phosphorylation of p53 on Ser15 and Ser392 increases its DNA-binding properties to cause an increased expression of p21 that may play a role in cell cycle arrest and/or apoptosis of HCT-116 cells.