Hiroki Shirasaki

Up-regulation of ICH-1l protein by thromboxane A2 antagonists enhances cisplatin-induced apoptosis in non-small-cell lung-cancer cell lines

Abstract We evaluated the effect of thromboxane A2 (TXA2) blockade on cisplatin-induced apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cisplatin induced apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with specific TXA2 antagonist, calcium 5(Z)-1R,2S,3S,4S-7-[3-phenylsul‐ fonylaminobicyclo[2.2.1]hept-2-yl]-5-heptonoate hydrate (S-1452) and 5(Z-6-{(1R,2R,3R,4S)-3-(N-4-bromoben‐ zenesulfonyl aminomethyl) bicyclo[2,2,1]heptane-2-yl}hex-5-enoic acid (ONO-NT-126), enhanced the cisplatin-induced apoptosis in each cell line. Acetyl-l-aspartyl-glutamyl-valyl-aspart-1-aldehyde (Ac-DEVD-CHO) inhibited cisplatin-induced apoptosis and enhancement of the apoptosis by TXA2 blockade, but acetyl-l-tyrosyl-valyl-alanyl-aspart-1-aldehyde (Ac-YVAD-CHO) had no effect on the apoptosis. There was no difference in the interleukin-1β-converting enzyme (ICE) protease protein expression in either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC-9/CDDP but was not changed by S-1452, cisplatin, or cotreatment with cisplatin and S-1452. Ice and Ced-3 homolog (ICH-1l) expression was significantly lower in PC-9/CDDP and was up-regulated by S-1452 or ONO-NT-126. These data suggest that ICH-1l might play a critical role in cisplatin-induced apoptosis and that TXA2 blockade up-regulates ICH-1l protein expression. Overexpression of ICH-1l and treatment with cisplatin might result in an increase in apoptosis in NSCLC cell lines.

Small cell lung cancer accompanied by lactic acidosis and syndrome of inappropriate secretion of antidiuretic hormone

Lactic acidosis is a rare complication in lung cancer. We report a case of lung cancer accompanied by both syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lactic acidosis. A 70-year-old man was referred to our hospital for examination of a left hilar mass shadow on a chest X-ray film. Small cell lung cancer (SCLC) was demonstrated by brushing the bronchial mucosa of the left lower lobe bronchus. His laboratory data showed SIADH and lactic acidosis that were probably due to SCLC. Fluid restriction improved SIADH, and combination chemotherapy for SCLC improved the lactic acidosis although the tumor size did not change.

A phase II trial of biweekly administration of vinorelbine (V) and gemcitabine (G) in elderly patients (Pts) with advanced non-small cell lung cancer (NSCLC)

7331 Objective: The purpose of this phase II trial was to evaluate the activity and the toxicity in elderly NSCLC pts of biweekly administration of this combination. Pts and Methods: 45 elderly pts with advanced NSCLC were treated with V 25mg/m2 intravenously and G 1000mg/m2 intravenously every 2 weeks. Eligible pts had: age ≥ 70 yrs; measurable or evaluable disease; ECOG PS 0-2; adequate bone marrow, liver and renal function; no previous chemo- or radiotherapy; life expectancy ≥12 weeks; written informed consent. RESULTS From August 2001 to November 2003, 46 pts were enrolled and 44 pts were eligible: males/females 27/17; median age 76(range 71-84); PS 0/1/2 25/16/3; stage IIIA/IIIB/IV 5/14/25; adeno/squamous 31/13. A total of 194 cycles(median 6/pt, range 1-12) were given. Tumor response and safety were analysed by December 2003. Of the 40 pts evaluable for response, 11(27.5%) had partial response and 19(47.5%) had stable disease. At this writing, median time to progression is 160 days and median survival is 397 days and 21 pts(47.7%) are still alive. All pts were evaluable for toxicity. Toxicity was mild and mainly hematologic. Grade 3/4 toxicities were neutropenia in 35.3/17.6% of pts, leukopenia in 29.4/2.3%, anemia in 0/0% and thrombocytopenia in 0%/2.9%, respectively. 2 pts(4.5%) had febrile neutropenia. Only 5(11.6%) pts had grade 3 or 4 non-hematological toxicities which were mainly constipation. There was one death from sepsis with neutropenia. At 40th Annual Meeting, we will demonstrate the final results of this trial. CONCLUSIONS This VG biweekly schedule shows an acceptable activity in elderly. The toxicity profile is favorable with mild myelotoxicity. No significant financial relationships to disclose.

Modulation of sensitivity to mitomycin C and a dithiol analogue by tempol in non-small-cell lung cancer cell lines under hypoxia

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: 7-N-(2-{[2-(γ-l-glutamylamino)ethyl]dithio}ethyl)mitomycin C, KW-2149, in non-small-cell lung cancer (NSCLC) cell lines under aerobic and hypoxic conditions. To investigate these mechanisms, we used MMC-resistant non-small-cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously reported that the MMC-resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resistant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant under hypoxic conditions after 2h exposure to MMC. However, on co-incubation with tempol, an inhibitor of the one-electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, was cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic conditions or by coincubation with tempol. There were no significant differences in the intracellular uptake of MMC and the activities of cytosolic detoxification enzymes between the PC-9 and PC-9/MC4 cell lines. These results support the hypothesis that the one-electron reduction pathway plays a partial role in the bioactivation of MMC, but not of KW-2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.