Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction. ' 2005 Wiley-Liss, Inc.Key words: MRP1; JNK; doxorubicin; small-cell lung cancer; multidrug resistance Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancer patients.1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro. One of the mechanisms of MDR is decreased accumulation of drug within cells because of reduced inward transport or increased drug efflux, such as overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. 3 P-glycoprotein (P-gp) that was cloned from KB-C 2.5 cells was the first ABC transporter identified. 4 Overexpression of P-gp has been detected in many multidrug resistant tumor cell lines and a variety of tumors from patients with both acquired and inherent drug resistance.5 Although P-gp is implicated in drug resistance in a number of tumor types, it is infrequently expressed in lung cancer cells. Another ABC transporter was cloned from the doxorubicin (DOX) resistant H69/AR SCLC cell line by Cole et al. 6 The transporter was designated as multidrug resistance-associated protein 1 (MRP1). The MRP family is now composed of 9 related ABC transporters that are able to transp...

The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significant decrease in the death rate was obtained, although neither treatment alone proved to be effective. A beneficial effect was also observed when CAM treatment was combined with surgical treatment. CAM showed no direct cytotoxicity to this tumor in vitro according to the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Spleen cells obtained from TB rats receiving CAM treatment showed a stronger tumor-neutralizing activity than those from rats which had not received CAM treatment (Winn assay). Enhanced induction of cytotoxic cells to allogeneic tumor was also observed in rats immunized with allogeneic tumor cells together with CAM treatment (51Cr release assay). The 13762NF tumor produces transforming growth factor-β (TGF-β), tumor necrosis factor alpha, and matrix metalloproteinase-9, and treatment of tumor cells with CAM in vitro for 24 h significantly inhibited the expression of the genes coding for these proteins (reverse transcription-PCR). Levels of expression of the TGF-β and interleukin-6 genes of spleen cells obtained from CAM-treated TB rats were both significantly lower than those of spleen cells from CAM-untreated TB rats. This study suggests that CAM has biological response modifier activities resulting in a beneficial therapeutic antitumor effect and might be useful for the treatment of human cancers.

Objective: Regimens with prolonged infusions of taxanes have been developed for patients with cancer to overcome drug resistance. Our objective of the present study was to examine the impact of prolonged exposure on the cytotoxicity of taxanes against non-small-cell lung carcinoma (NSCLC) cell lines and the clinical response and outcome of the patients. Methods: Five cell lines (NCI-H2882, -H2887, -H2973, -H3122, -H3255) were derived from previously untreated patients with NSCLC who participated in clinical trials of continuous 96-hour infusions of paclitaxel followed by bolus cisplatin. Two additional cell lines (NCI-H838, -H1299) with previously published data were used as controls. Drug sensitivities were assessed by the MTS (Promega) assay. Multidrug resistance (MDR) phenotypes were assessed by quantitative real-time PCR and HER-2/neu by both immunohistochemistry and ELISA. Results: The median of mean IC₅₀ values of docetaxel at the exposure durations of 3, 24, 72 and 120 h were 0.52, 0.06, 0.03 and 0.06 µM, respectively. The median of mean IC₅₀ values of paclitaxel at the exposure duration of 3, 24, 72 and 120 h were 0.48, 0.13, 0.03 and 0.02 µM, respectively. In all cell lines studied, there was a less than 4-fold difference in the IC₅₀ values between docetaxel and paclitaxel at 3-, 72-, and 120-hour exposure times. The single cell line with moderate MDR1 expression (NCI-H2887) was the only cell line established from a patient with progressive disease when treated with paclitaxel. Conclusions: This study demonstrates prolonged exposure to both docetaxel and paclitaxel inhibits the growth of NSCLC cell lines in similar fashion.

Ionizing radiation (IR) is known to upregulate cell surface Fas through p53 activation in various cells. However, the signaling pathway intermediating between p53 activation and cell surface Fas upregulation remains to be elucidated. Recently, Fas-associated phosphatase-1 (FAP-1) has been reported to associate with Fas and inhibit cell surface Fas expression. We evaluated the expression of FAP-1 mRNA following IR in A549 cells. Ionizing radiation inhibited the expression of FAP-1 mRNA. Pretreatment with p53 inhibitor pifithrin a cancelled the IR-induced downregulation of FAP-1 mRNA. These results suggest that IR-induced p53 activation may upregulate cell surface Fas via the down-modulation of FAP-1.

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Summary When cyclophosphamide (CY) (100-120 mg kg-') was administered intravenously (i.v.) to normal F-344 rats, oliguria occurred over the 5-day observation period. Conversely, in rats bearing matrix metalloproteinase-9 (MMP-9) producing 1 3762NF mammary adenocarcinoma (MTLn3 clone), polyuria occurred chiefly during the first 24 h after CY treatment. In parallel with urine volume, a decrease in the urinary excretion of Nacetyl-beta-D-glucosaminidase (NAG) was observed during the first 5 days after CY treatment in normal rats, but it increased in MTLn3-bearing rats. No elevation in blood urea nitrogen (BUN) or serum creatinine (Cr) values was observed for either group. Both urine volume and urinary excretion of NAG after CY treatment were lower in rats bearing the MTC clone (lower production of MMP-9) than for those bearing the MTLn3 clone. In the case of treatment with cisplatin (CDDP, 4-6 mg kg-'), urine volume, urinary NAG excretion and BUN and serum Cr values all increased in normal rats and were all found to be higher in MTLn3-bearing rats than in normal rats. The diuretic response to these drugs in tumour-bearing (TB) rats may be associated with MMP-9 produced by the tumour cells. This report suggests that the nephrotoxicity due to anti-cancer drugs may change when the drugs are used for the treatment of patients bearing a MMP-9-producing tumour.Keywords: cyclophosphamide; matrix metalloproteinase-9; nephrotoxicity; cisplatin

We present a case of thymic carcinoid, in which primary and metastatic lesions of lymph nodes and bones could be detected by [(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET, but not by (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, or by (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy. FDG-PET may be a useful tool for managing thymic carcinoids in patients with negative results on (123)I-MIBG SPECT or (99m)Tc-MDP imaging.

Diffuse parenchymal infiltrates in lower lung fields, right pleural effusion, multiple bronchial stenoses and hepatosplenomegalywere observed in a 30-year-old womanwith iritis. Pleural effusion was a yellow exudate which was predominantly lymphocytic. A pulmonary function test showedan obstructive pattern, and multiple bronchial stenoses were observed on bronchoscopy. Both transbronchial lung biopsy (TBLB) and bronchial mucosal biopsy failed in demonstrating non-caseating granulomas, but liver biopsy revealed granulomas consistent with sarcoidosis. This is a very rare case, in which pleural effusion and bronchial stenoses occurred in the same patient. (Internal Medicine 36: 637-639, 1997)