Tissue platinum concentration and tumor response in non-small-cell lung cancer.
ABSTRACT PURPOSE Platinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. PATIENTS AND METHODS We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. Results Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles. CONCLUSION This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.
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ABSTRACT: There are currently no available biomarkers for advanced pleural mesothelioma that determine which patients could benefit from a specific chemotherapy regimen. Based on the results of a previously published phase II study, we associated the (99m)Technetium-labelled liposomal doxorubicin ((99m)Tc-LD) uptake value (75 % cut-off) with the response rate, progression-free survival and overall survival of patients treated with a combination of liposomal doxorubicin and cisplatin. Patients with tumours exhibiting increased (99m)Tc-LD uptake showed better response rates, progression-free survival and overall survival than those exhibiting lower uptake 73.3 versus 15 % (p < 0.001); 6.9 versus 3.2 months (p = 0.033) and 23 versus 6.6 months (p = 0.001), respectively. (99m)Tc-DL uptake in tumour tissue could define a set of patients who would benefit from this chemotherapy regimen.Cancer Chemotherapy and Pharmacology 05/2014; · 2.80 Impact Factor
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ABSTRACT: Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens. We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians. To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.Lung cancer (Amsterdam, Netherlands) 04/2014; · 3.14 Impact Factor
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ABSTRACT: Cisplatin [cis-diammineplatinum dichloride (DDP)] resistance is a major limitation in the treatment of lung cancer. We previously demonstrated that DDP dissolved in 5% ethanol (5% ethanol-DDP) injected intratumorally was able to eradicate DDP-resistant lung tumors and prolong survival, as 5% ethanol improved DDP delivery to the tumor. The present study aimed to investigate the efficacy of DDP in various concentrations of ethanol and determine the optimal ethanol concentration in which DDP exhibits optimal efficacy in reducing tumor volume and prolonging survival. The efficiency of DDP dissolved in 2, 5, 10, 20 and 50% ethanol (v/v) in DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice was investigated. Tumor growth and survival were evaluated in all the treatment groups. Microvessel density in xenograft tumor tissues was measured by immunohistochemistry. Our results revealed that 5% ethanol-DDP exhibited the highest efficiency in reducing tumor volume and prolonging survival among all the investigated ethanol-DDP combinations. We found that 5% ethanol-DDP produced the most significant inhibition of tumor angiogenesis among all the remaining ethanol-DDP combinations, while treatment with ethanol alone increased tumor angiogenesis. In conclusion, 5% ethanol-DDP produced the strongest tumor growth inhibition and longest survival among all the investigated ethanol-DDP combinations, possibly providing a novel therapeutic strategy for improving the survival of patients with DDP-resistant lung cancer. The potent inhibition of tumor angiogenesis by 5% ethanol-DDP may be one of the mechanisms underlying its superior efficiency.Molecular and clinical oncology. 07/2014; 2(4):491-496.