Picoplatin overcomes resistance to cell toxicity in small-cell lung cancer cells previously treated with cisplatin and carboplatin.
OBJECTIVE
Picoplatin is a new generation platinum designed to overcome platinum resistance. The goal of this study was to assess picoplatin anti-tumor activity and measure various cellular parameters in small-cell lung cancer (SCLC) cells resistant to cell killing by cisplatin and carboplatin.


METHODS
We developed several platinum-resistant SCLC cell lines to evaluate picoplatin activity and drug resistance mechanisms in vitro. Drug cytotoxicity was measured by MTS assay. Total cellular platinum accumulation was measured by inductively coupled plasma mass spectrometry (ICP-MS). Whole genome gene expression profiling was carried out by microarray analysis.


RESULTS
Picoplatin retained significant cytotoxic activity in platinum-resistant SCLC lines compared to cisplatin and carboplatin. Cellular picoplatin accumulation in platinum-resistant and parental cells was high relative to levels of cellular platinum found in the same cell lines after cisplatin or carboplatin treatment. Gene expression analyses revealed substantial differences in gene expression and highlighted specific annotation clusters in carboplatin-resistant cells. In addition, a similar gene expression pattern was observed in picoplatin-treated carboplatin-resistant and parental cells.


CONCLUSIONS
Our study demonstrates that picoplatin can overcome carboplatin and cisplatin resistance. The results suggest decreased platinum accumulation as a potential mechanism of platinum resistance in SCLC cells, provide candidate markers (e.g. several genes in the Hox, glutathione biosynthetic process, and MAGE families) that may serve as signatures for platinum resistance, support distinct effects of picoplatin on SCLC cells compared to other platinums, and provide a rationale to develop picoplatin for the treatment of recurrent SCLC following initial therapy with cisplatin or carboplatin.
Tang
Chi-Hui
CH
Poniard Pharmaceuticals, Inc, South San Francisco, CA, USA. chi_hui.tang@yahoo.com
Parham
Christi
C
Shocron
Ellyn
E
McMahon
Gerald
G
Patel
Neela
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D055752:Small Cell Lung Carcinoma
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II); D016190:Carboplatin; D002945:Cisplatin
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