[Show abstract][Hide abstract] ABSTRACT: Melanoma is a highly aggressive tumor of melanocytes. The efficacy of different cytotoxic chemotherapy regimens does not exceed
20%. The search for markers for patient sensitivity to chemotherapy provides a rational basis for the development of cytotoxic
chemotherapy. In this study, we evaluated six blood lymphocyte parameters (the efficacy of BER and MMR; the expression of
MLH1, MSH2, FasR; and cell death) as prognostic markers for melanoma chemotherapy. We found that chemotherapy induced AP sites
and ssDNA breaks in lymphocytes repaired through the BER pathway. However, ssDNA breaks were completely repaired after chemotherapy
and, therefore, did not contribute to the toxic effect of chemotherapy. dsDNA breaks produced by a functioning MMR system
appeared downstream of methylation adducts, which was confirmed by the linear correlation of these parameters in various patients.
The number of dsDNA breaks, but not MMR, MLH1, and MSH2 expression, correlated to the efficacy of chemotherapy. A positive
correlation was observed between lymphocyte death induced by chemotherapy and the patient’s clinical response, which may show
that the nucleotide excision repair (NER) mechanism is implicated in the generation of double-strand breaks and the cytotoxic
effect of chemotherapy.
Keywordsmelanoma–lymphocytes–chemotherapy–cell marker–DNA breaks–DNA repair
No preview · Article · Feb 2011 · Cell and Tissue Biology
[Show abstract][Hide abstract] ABSTRACT: Melanoma is a highly aggressive neoplastic disease attributed to transformed melanocytes. The efficacy of regimens of cytotoxic chemotherapy for advanced stage patients does not exceed 20%. Search for lymphocyte markers of patients' sensitivity to chemotherapy provides a rational basis for development of cytotoxic chemotherapy. Using blood lymphocytes we evaluated efficacy of BER and MMR, expression of MLH1, MSH2 and FasR, and cell death in melanoma patients relative to clinical response to chemotherapy. We found that LDCI-chemotherapy (lomustine, dacarbazine, cisplatin and interferon gamma), induced AP sites and DNA ss-breaks which repaired trough BER pathway. However, neither initial DNA damage nor the rate of their repair correlated with clinical response. This result prompts us to think that this type of damage is not crucial in cytotoxic effect of LDCI-regimen of chemotherapy. DNA ds-breakes appeared downstream ss-breakes were attributed to repair of 06-methylguanine by MMR mechanism in PHA-stimulated lymphocytes. The number of ds-breakes appeared by 48 correlated with positive clinical response of patients to chemotherapy. The same link was observed between clinical response and the number of dead lymphocytes. However, there was no correlation between clinical response and expression of MLHI + MSH2 and FasR. These results imply possible contribution of crosslink repair through NER pathway to formation of DNA ds-breaks as well as to cytotoxicity of LDCl-therapy. The observed link between high level of secondary ds-breaks and positive response to chemotherapy indicates the potential of these instruments to serve as prognostic end point in clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Patients with advanced malignant melanoma have poor prognosis as conventional chemotherapy induces complete response in a very small fraction (not more than 20%). One of research strategies aimed at raising its efficiency is the search for markers predicting individual response to chemotherapy. Our study was concerned with evaluation of the potential of DNA damage, repair (BER, MMR), expression of proteins MLH1, MSH2 and FasR as prognosticators of chemotherapy. These parameters were assessed in lymphocytes sampled from the blood of patients with metastatic cutaneous melanoma before and after one cycle of chemotherapy with lomustine, dacarbazine, cisplatin and interferon-gamma (LDCI). Clinical response was evaluated after a full course of therapy. We established that the major DNA damage induced by chemotherapy occurred on the levels of AP sites and single strand (SS) breaks. Despite the individual variations in BER efficacy, complete repair of SS breaks was reported in lymphocytes of all patients 30 days after the first cycle of chemotherapy. As a consequence, this type of damage and relevant BER efficacy did not correlate with clinical response. Conversely, the number of DNA double strand breaks detected in lymphocytes after the first cycle of chemotherapy was in good correlation with positive clinical response (p < 0.001). This parameter does not fully represent MMR function and, if coupled with cytotoxic effect of chemotherapy on lymphocytes, may be used as a predictive marker for clinical response to LDCI chemotherapy regimens for melanoma.
No preview · Article · Jan 2011 · Voprosy onkologii
[Show abstract][Hide abstract] ABSTRACT: Melanoma is among the most aggressive malignancies. Tumors with a thickness of 4 mm can produce metastases, and the mean survival
of the patients is 9 months. The review presents modern classification of the melanoma types based on cytological and morphological
indices (Clark model). Alterations of genes in melanomas are discussed in detail. These genes include tumor suppressors, proliferative
response genes (oncogenes), and transcription factors. Alterations in the Wnt signaling, MAPK cascade, and Fas signaling pathways
are considered. Changes in the mismatch repair (MMR) genes are also analyzed. From practical perspective, understanding the
genetic alterations provides identification of potential targets for therapeutic exposure and enables prognosis of the tumor
response to chemotherapy.
No preview · Article · Feb 2010 · Russian Journal of Genetics