Cisplatin (CDDP)-based chemotherapy is the standard of care in patients with muscle-invasive bladder cancer. However, in a large number of cases, the disease becomes resistant or does not respond to CDDP, and thus progresses and disseminates. In such cases, prognosis of patients is very poor. CDDP manifests its cytotoxic effects mainly through DNA damage induction. Hence, response to CDDP is mainly dependent on DNA damage repair and tolerance mechanisms. Herein, we have examined CDDP response in a panel of the urothelial carcinoma cell (UCC) lines. We characterized these cell lines with regard to viability after CDDP treatment, as well as kinetics of induction and repair of CDDP-induced DNA damage. We demonstrate that repair of CDDP-induced DNA lesions correlates, at least to some extent, with CDDP sensitivity. Furthermore, we monitored expression of the key genes involved in selected DNA repair and tolerance mechanisms, nucleotide excision repair, homologous recombination and translesion DNA synthesis, and show that it differs in the UCC lines and positively correlates with CDDP resistance. Our data indicate that CDDP response in the UCC lines is dependent on DNA damage repair and tolerance factors, which may, therefore, represent valuable therapeutic targets in this malignancy.
e16615 Background: Cisplatin (CDDP) is the key agent in treatment of muscle-infiltrating urothelial carcinomas (MIUCs). However, around a half of patients do not respond to combined chemotherapy based on this agent what might be caused by an increased capacity to repair CDDP-induced DNA damage. The objective of this study was to determine the levels of selected DNA repair and tolerance factors in patients with MIUC to reveal their potential prognostic value. Methods: We have evaluated the bladder tumors from 86 subjects reviewed by trained pathologists. Median age was 67 years (range 37-84 years), 75.6% were males. All patients had MIUCs. To detect the XPA, XPF, POLI, REV3L, and POLH levels in primary tumors, immunohistochemistry was used. Study population was divided into two groups by positivity defined as 76-100% (negative vs positive tumors). Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: At median follow-up of 20.6 months (1.0-212.5 months), 86.1% of patients died. Median OS of subjects with tumors stained negative for XPA, XPF, REV3L, and POLH did not differ significantly from patients with positive staining for these proteins, with hazard ratios (HRs) being 0.61, 0.62, 0.98, and 0.72, respectively. Patients with tumor negative for POLI expression had significantly ( p = 0.0334) better median OS of 23.5 months (range 17.3-47.3 months) compared to subjects with tumor stained positive for expression of this protein [median OS of 17.6 months (range 13.6-21.3 months)] (HR = 0.61, 95%, CI 0.39-0.97). Conclusions: In this study, we showed a clear correlation between higher POLI expression in primary tumor tissue and inferior outcome in MIUC patients. Hence, we believe that the expression level of POLI might represent a prognostic biomarker and potentially constitute promising therapeutic target.
e16055 Background: TGCTs are an excellent example of chemosensitive disease. However, cisplatin-based chemotherapy has significant side effects, including myelosuppression. Previously, we found endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) to be an independent prognostic marker. We tested the hypothesis that patients with high endogenous DNA damage levels in PBMCs have an increased risk of developing hematologic toxicity. Methods: 120 chemotherapy-naïve patients with TGCTs treated in the National Cancer Institute and the St. Elisabeth Cancer Institute in Bratislava, Slovakia, from 2012 to 2018 were enrolled. All patients received platinum-based chemotherapy with G-CSF support. On the day of starting treatment, we measured the endogenous DNA damage levels in PBMCs using the Comet assay. We used a cut-off level of 5.25, a value previously found to stratify patients based on their prognosis. We monitored hematologic toxicity during the 1st cycle of chemotherapy. The mean and SEM were calculated for all variables. Results: Patients with high DNA damage levels ( > 5.25) had more significant hematologic toxicity with significantly lower nadir white blood cell count (6.0±1.1×109/L vs 9.8±1.0×109/L p = 0.001), absolute neutrophil count (4.1±1.0×109/L vs 7.0±0.9×109/L p = 0.013) and absolute lymphocyte count (ALC, 1.1±0.1×109/L vs 1.5±0.1×109/L p < 0.001). ALCs on day 0 (1.5±0.1×109/L vs 1.8±0.1×109/L p = 0.005) and day 22 (2.0±0.1×109/L vs 2.4±0.1×109/L p = 0.046) were also significantly lower in patients with high DNA damage levels. There were no significant differences in hemoglobin levels or platelet counts between the two groups. Neutrophil to lymphocyte ratio and systemic immune-inflammation index were lower at nadir in patients with high DNA damage levels, however, these differences were not statistically significant (p = 0.08 and p = 0.10, respectively). Conclusions: This study shows that higher endogenous DNA damage levels correlate with an increased risk of hematologic toxicity. The Comet assay data can be used to select patients for closer monitoring due to a higher risk of acute chemotherapy-related complications.
e16020 Background: Cisplatin-based combination chemotherapy is used as a standard neoadjuvant treatment of patients with muscle-infiltrating urothelial bladder carcinoma (MIUBC). DNA damage represents one of the most important factors contributing to its toxicity. The objective of this prospective study is to evaluate the prognostic value of the endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) from MIUBC patients before treatment with neoadjuvant chemotherapy. Methods: PBMCs isolated from 25 consecutive MIUBC patients (16 men, 64%) were included into this study. Karnofsky index < 80% was present in 1 patient (4%). DNA damage levels in PBMCs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. Cut-off of 5.25 was used to dichotomize DNA damage level as “high” or “low” based on the previous study. Results: At the median follow-up 12.1 months, 13 patients progressed (52%) and 8 patients (32%) died. The median and IQR (interquartile range) of endogenous DNA damage level was 7.52 (4.07-27.9). Patients with low DNA damage levels had non-significantly better progression free survival (HR = 0.33, 95% CI: 0.09-1.29) and overall survival (HR = 0.64, 95% CI: 0.11-3.87) compared to patients with high DNA damage levels. Conclusions: These data suggest that endogenous DNA damage levels in PBMCs from MIUBC patients may serve as a prognostic marker early identifying patients with poor outcome. This study is supported by VEGA 2/0053/19 and APVV-17-0384.
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