PubMed · 7694459
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C W Hankal. 1993. A glimpse beyond.. https://doi.org/10.1097/00000446-199311000-00040
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The development of non-P-glycoprotein-mediated multi-drug resistance is a frequent event among lung-cancer cell lines. In an attempt to understand the underlying mechanisms of this phenotype, we have selected a multi-drug-resistant subline (POGB/DX) in vitro for doxorubicin resistance. The original cell line (POGB) was established in vitro from a non-treated patient with a small-cell lung cancer. POGB/DX cells were cross-resistant to other drugs, associated with MDR phenotype. In contrast, they were not resistant to taxol, camptothecin or melphalan, but were instead hypersensitive to 5-fluorouracil. Although expression of the mdr-1 gene was not detected in POGB/DX cells, cellular pharmacokinetics showed a reduced drug accumulation and altered intracellular localization in the POGB/DX cell line. This defect in drug accumulation was associated with overexpression and amplification of the MRP gene. Interestingly, verapamil, a known modulator of P-glycoprotein function, was able to reverse drug resistance and to increase drug accumulation. In Northern-blot analysis no differences in expression of topoisomerase I and II (alpha and beta), DNA polymerase beta, or HSP70 and HSP60 genes were observed between POGB and POGB/DX. Coupled to lack of changes in expression of known resistance factors, overexpression of MRP and modulation by verapamil strongly support a role for this gene product in the development of drug resistance in this SCLC cell system. This study provides evidence that (a) altered cellular pharmacokinetics is related to MRP expression; (b) MRP-mediated phenotype is characterized by a specific pattern of cross-resistance, which does not involve taxol; and (c) verapamil may be effective in modulating the function of the MRP gene product.
Three patients with small cell carcinoma of the lung presented with a persistent unpleasant sweet taste as their initial and only symptom. On further evaluation, they were found to have hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone. In each case, resolution of the sweet taste paralleled an increase in serum sodium concentration after water restriction alone. Linkage of the sweet taste with a low serum sodium concentration strongly implicates hyponatremia--rather than tumor, antidiuretic factor, medications, or chemotherapy--as the central mechanism responsible for this previously unreported (to our knowledge) sentinel symptom of small cell carcinoma of the lung.
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