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Animal studies suggest that the kidney is involved in the elimination of recombinant human granulocyte colony-stimulating factor (rhG-CSF), which is used for patients with neutropenia during cancer chemotherapy. Since anticancer drugs induce nephrotoxicity, it is important to clarify the role of the kidney in the pharmacokinetics of rhG-CSF in cancer patients. Our study was designed to evaluate the relationship between the pharmacokinetics of rhG-CSF and renal function in lung cancer patients compared to the absolute neutrophil count (ANC). The pharmacokinetic studies were conducted with 25 lung cancer patients. Following chemotherapy using platinum-based compounds, a bolus 5 microg of rhG-CSF/kg of body weight was intravenously injected from the first day of leukopenia or neutropenia. Pharmacokinetic parameters were estimated by fitting the concentration in serum-time data to a two-compartment model according to the population pharmacokinetics and the Bayesian method. Creatinine clearance (CL(CR)) was predicted by the Cockcroft-Gault formula. rhG-CSF clearance (CL(G-CSF)) correlated significantly with the ANC (r = 0.613; P < 0.001) and CL(CR) (r = 0.632; P < 0.001). Multiple linear regression analysis showed that the combination of the ANC and CL(CR) accounted for 57.4% of the variation of CL(G-CSF). In patients with an ANC of <1,000/microl, CL(CR) accounted for 72.9% of the variation of CL(G-CSF) (P < 0.001). Our findings suggest that renal function and neutrophil counts correlate with CL(G-CSF) and that the role of renal function in eliminating rhG-CSF is important in lung cancer patients with neutropenia.

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An angular analysis of B0-->J/psiK(*0) and B(0)(s)-->J/psistraight phi has been used to determine the decay amplitudes with parity-even longitudinal ( A0) and transverse ( A( parallel)) polarization and parity-odd transverse ( A( perpendicular)) polarization. The measurements are based on 190 B0 and 40 B(0)(s) candidates obtained from 89 pb(-1) of &pmacr;p collisions at the Fermilab Tevatron. The longitudinal decay amplitude dominates with |A0|(2) = 0.59+/-0. 06+/-0.01 for B0 and |A0|(2) = 0.61+/-0.14+/-0.02 for B(0)(s) decays. The parity-odd amplitude is found to be small with |A( perpendicular)|(2) = 0.13(+0.12)(-0.09)+/-0.06 for B0 and |A( perpendicular)|(2) = 0.23+/-0.19+/-0.04 for B(0)(s) decays.

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To investigate interactions between the multidrug resistance protein (MRP) and antimicrobial agents, we examined the effects of 12 agents on vincristine sensitivity and efflux of the calcein acetoxy-methyl ester (calcein-AM) of a MRP substrate in MRP-overexpressing cells. Only ofloxacin and erythromycin enhanced sensitivity with increased intracellular vincristine accumulation and inhibited the calcein-AM efflux. Our findings suggest that the two agents are possible MRP substrates and may competitively inhibit MRP function as a drug efflux pump.

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MS-209 is a novel quinoline derivative reversing P-glycoprotein-mediated multidrug resistance (MDR). We investigated the interaction between MS-209 and multidrug resistance protein (MRP) in MRP-overexpressing human gastric cancer cells. We measured [3H]leukotriene C4 uptake into the membrane vesicles of the cells and intracellular calcein and [3H]vincristine accumulation with or without MS-209. In multi-drug-resistant MKN45R0.8 cells selected by doxorubicin, MS-209 dose dependently reduced MRP-mediated [3H]leukotriene C4 uptake and increased calcein accumulation. In both resistant and unselected cell lines expressing the MRP gene, MS-209 increased [3H]vincristine accumulation in proportion with the level of MRP mRNA expression and enhanced the cytotoxicity of etoposide, doxorubicin, and vincristine. The reversal effects correlated with the level of MRP mRNA expression in these cells. Our results indicate that MS-209 effectively reverses intrinsic and acquired MRP-mediated MDR of gastric cancer cells by interacting directly with MRP.

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Irinotecan (CPT-11) and carboplatin have broad anti-tumor activities. We conducted a Phase I study of CPT-11 combined with carboplatin in previously untreated solid cancers, especially advanced lung cancer. The aim of the study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this regimen. In addition, we prospectively evaluated the Chatelut formula for predicting carboplatin clearance. Patients with advanced cancer were treated with CPT-11 (days 1, 8, and 15) and carboplatin (day 1) of a fixed-target area under the concentration-time curve (AUC) of 5 mg x min/ml. Carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The CPT-11 dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2. A total of 27 patients, 26 lung cancer patients and 1 colon cancer patient, were enrolled in this study. Dose-limiting leukoneutropenia, thrombocytopenia, and diarrhea, including one treatment-related death, were observed at 60 mg/m2 CPT-11, indicating that this level was the MTD. In 11 patients, the actual AUCs of carboplatin almost achieved the target AUC of 5. Fifteen (60%) of 25 evaluable patients showed an objective response, with an 85% response rate [11 of 13 patients (complete response, 31%; partial response, 54%)] in small cell lung cancers and a 36% response rate (4 of 11 patients) in non-small cell lung cancers. Neutropenia, thrombocytopenia, and diarrhea were the dose-limiting toxicities in this regimen. CPT-11 (50 mg/m2) under the carboplatin target AUC of 5 using the Chatelut formula was the recommended dose for further Phase II study, and this regimen seems to be active for small cell lung cancer.

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Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988-991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 microg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 +/- 132 versus 995 +/- 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% +/- 22.1%) and high at neutrophilia with rhG-CSF therapy (73. 0% +/- 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r2 = 0.91; P < 0.0001) and neutrophil count (r2 = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.

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ONO-1078 is a new class of peptide leukotriene receptor antagonist, and multidrug resistance protein (MRP) is a membrane tranporter of multiple anticancer drugs and endogenous leukotriene C4 (LTC4). We investigated the effects of ONO-1078 on drug sensitivity and LTC4-efflux in MRP-expressing lung cancer cells. Drug sensitivity, intracellular vincristine accumulation, and intracellular and extracellular LTC4 concentrations were measured with or without ONO-1078. The effect of ONO-1078 on MRP-mediated calcein-efflux was determined by flow cytometry. ONO-1078 (1 to 10 microM) dose-dependently enhanced the sensitivity of NCI-H520 cells to vincristine with the reduced accumulation, and also enhanced the sensitivity to doxorubicin and etoposide. ONO-1078 inhibited both LTC4- and calcein-efflux from the cells with increased intracellular accumulations. Our findings indicate that ONO-1078 modulates multidrug resistance and inhibits LTC4-efflux in lung cancer cells, by inhibition of MRP function.

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Lung resistance-related protein (LRP) is the human major vault transporter protein and is suggested to confer anticancer drug resistance. We quantitated the level of LRP mRNA expression in 10 gastric and 14 lung cancer cell lines by RT-PCR, and examined the relationship between its level in these cells and their sensitivities to anticancer drugs. HT1080 fibrosarcoma cells were used as positive controls for LRP. LRP mRNA was expressed in all gastric and lung cancer lines, and its level in each cell type was less than two-fold that of HT1080 cells, except for two lung cancer lines. The correlation between the level of LRP mRNA expression and cisplatin sensitivity was significant in lung cancer lines (r = 0.762, P = 0.028), and borderline in gastric cancer lines (r = 0.631, P = 0.129). There was no correlation between the level of LRP mRNA expression and etoposide, doxorubicin, vincristine, or SN-38. Our results suggest that LRP is commonly expressed in gastric and lung cancers, and may confer their resistance to cisplatin.

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Multidrug resistance-associated protein (MRP) mRNA expression and drug sensitivity in lung cancer cells were examined, and the effects of verapamil, a modulating agent for MRP, on drug sensitivity were also tested. Nine cell lines expressed various levels of MRP gene expression but not the MDR1 gene. The levels were higher in non-small cell carcinoma cells (NSCLC) than in small cell carcinoma cells (SCLC). Clear correlations between the MRP gene level and the sensitivity to etoposide (VP-16) and doxorubicin (Dox) were observed except for one cell line which highly expressed DNA topoisomerase II. Positive correlations between the MRP gene levels in three cell lines and the modulation effects of verapamil in VP-16, Dox, and vincristine were observed. The present results indicate that MRP probably confers intrinsic multidrug resistance in NSCLC rather than in SCLC.

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A 47-year-old man with dermatomyositis and interstitial pneumonia had been treated with prednisolone since May, 1992, and with azathioprine since April, 1993. During the sixth month of this treatment, primary pulmonary non-Hodgkin's lymphoma (T-cell, diffuse, pleomorphic) developed. Chemotherapy (vincristine and adriamycin) was begun but there was no response. An invasive lesion of the brain was seen on a CT image. Despite cranial radiotherapy, the patient died of respiratory suppression due to progressive brain disease on December 14, 1993. Primary pulmonary non-Hodgkin's lymphoma develops only rarely in patients with dermatomyositis. In this case, oncogenesis may have been related to the use of immunosuppressants.

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A 32-year-old immunocompetent man developed fever and malaise that persisted for three years. As he had no health insurance, he never received any medical treatment. On admission, chest X-ray revealed multiple cavitary lesions and his sputnum yielded acid-fast bacilli, that were identified as Mycobacterium kansasii with multidrug resistance. Although his general status improved transiently by antituberculous agents, he died of respiratory insufficiency after four months. The prognosis of Mycobacterium kansasii pulmonary disease is reported to be relatively good among non-tuberculous mycobacteriosis, however, physicians must pay careful attention to cases of delayed start of therapy or multidrug resistance, or both.

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Ifosfamide chemotherapy was studied in 20 patients with advanced pancreatic carcinoma. It was administered at a dose of 1.2-1.5 g/body/day for 5 consecutive days every 3-4 weeks, and the patients treated over 2 courses were registered in our trial. Eleven patients had not received prior chemotherapy. Results achieved were as follows: PR in one patient, NC in 9 patients, and PD in 10 patients. The response rate was 5% and the median survival time was 17 weeks. Toxic effects included anorexia (80%), nausea and vomiting (65%), alopecia (20%), mental disturbance (20%), granulocytopenia (20%), thrombocytopenia (5%), and no renalurological disturbance. We concluded that ifosfamide was not effective for chemotherapy of advanced pancreatic carcinoma.

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To elucidate whether gene alterations of topoisomerase I (topo I) exist in untreated non-small cell lung carcinomas (NSCLC), polymerase chain reaction-single strand conformation polymorphism analysis was performed in forty-four NSCLC tissue samples. Gene alterations of topo I were sought in three regions, near codons 361 and 363, 533, and 722 and 729, where point mutations have been found in resistant tumor cell lines selected by chronic camptothecin exposure. In addition, nuclear topo I contents were determined by immunoblotting. No mobility shifts were observed compared to the pattern observed in a normal control at any of the three regions in any sample, whereas topo I levels showed an approximately 12-fold variation. The variation is remarkably large compared to those seen in previous in vitro and in vivo studies. The results suggest that mutations of topo I may not contribute to intrinsic resistance of NSCLC to camptothecins, but low topo I levels may account, at least in part, for the resistance.

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PURPOSE AND METHODS: MS-209 is a newly synthesized quinoline compound used orally to overcome human P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). The multidrug resistance-associated protein (MRP) gene is thought to play an important role in MDR in lung cancer. To investigate whether MS-209 could also overcome MRP-mediated MDR, we examined the effect of the compound using a cytotoxicity assay on MDR1 gene-negative drug-selected MDR and wildtype lung cancer cells with various levels of MRP gene expression. The effects of MS-209 were compared with those of verapamil (VER) and cyclosporin A (CsA). The level of MRP gene expression in the cells was evaluated semiquantitatively by RT-PCR. For vincristine (VCR), intracellular accumulation of [3H]-VCR was measured with or without MS-209. RESULTS: In MDR UMCC-1/VP small-cell lung carcinoma cell line, 5 microM of MS-209 and VER enhanced the cytotoxicity of etoposide, doxorubicin (DOX) and VCR more than twofold, and completely reversed the resistance to VCR. The mean reversing effects of MS-209 on DOX and VCR were significantly stronger than those of VER and CsA. In wildtype non-small-cell lung carcinoma cells, the effects of MS-209 were almost equal to those of VER and CsA. The effect of these three agents correlated with the level of MRP gene expression. The MS-209-induced increase in intracellular accumulation of VCR was proportional to the level of MRP gene expression in these cells. CONCLUSION: Our results indicate that MS-209 is a potentially useful drug that can overcome MRP-mediated intrinsic and acquired MDR in human lung cancer.

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A 54-year-old nonsmoker female developed atelectasis of the anterior basal segment of the right lower lobe. A non-pulsating endobronchial tumor was observed bronchoscopically obstructing the right basal bronchus. The tumor was confirmed on arteriography to be a saccular aneurysm of the right bronchial artery. The aneurysm was treated with bronchial artery embolization. Bronchial artery aneurysm, without a predisposing disease, is quite rare, but should be considered as an etiological factor of atelectasis.

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Metallothioneins (MTs) are induced by various stimuli and probably confer drug resistance in tumor cells in vitro. To investigate whether MT expression in lung cancer is induced by chemotherapy, ninety-seven surgical specimens from patients who had or not received chemotherapy containing cisplatin, were stained immunohistochemically for MT. In untreated tumors, 23% (15/64) of all tumors and 27% (15/56) of non-small-cell carcinoma (NSCLC) stained positive, while all eight small-cell carcinoma (SCLC) were negative. In treated tumors, 52% (17/33) of all tumors, 80% (12/15) of NSCLC and 28% (5/18) of SCLC stained positive. The proportion of positively-stained tumors was significantly higher in treated NSCLC compared with untreated NSCLC (P = 0.0005) and treated SCLC (P < 0.005). Our results indicate that MT expression increases following chemotherapy and that such expression may confer during resistance in lung cancer, especially NSCLC.

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We performed immunohistochemical staining of glutathione S-transferase-pi (GST-pi) in 97 lung cancer specimens. In untreated patients, 86% (48/56) of NSCLC and none (0/8) of SCLC stained for GST-pi, and all squamous cell carcinomas were positive (28/28). The proportion of positive NSCLC with preoperative chemotherapy was similar to that of the untreated NSCLC, but the proportion of treated SCLC positive for GST-pi (14/18) was significantly higher than untreated tumors. GST-pi in NSCLC may be a tumor marker rather than being involved in drug resistance, and GST-pi-induction by chemotherapy may relate to acquired resistance in SCLC.

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To determine the expression of multidrug resistance-associated protein (MRP) gene and its role in gastric and colon cancers, we analyzed 10 gastric and 10 colon non-drug-selected cell lines and a similar number of tissue samples of these cancers. We compared the expression of MRP and mdrl mRNA in cell lines and tissues using reverse-transcriptase polymerase chain reaction. In mdrl-negative cells, the relationship between the level of MRP gene expression and sensitivity to anticancer drugs was examined. The effect of verapamil, an MRP-modulating agent, was also examined in these cells. The expression of MRP gene in gastric cancer cell lines varied from a low to a high level, but mdrl was not detected in any of these cell lines. Colon cancer cell lines expressed low to intermediate levels of MRP gene, and half of the cells co-expressed low to high levels of mdrl. In tissue samples, the expression pattern of the two multidrug resistance (MDR) genes was broadly similar to that described for the cell lines, except that most of the gastric cancer tissue samples did express low levels of mdrl. No significant correlation was observed between the level of MRP gene expression and sensitivity to anticancer drugs in gastric and colon cell lines. However, verapamil significantly increased the sensitivity to etoposide, doxorubicin and vincristine in cells highly expressing MRP gene. Our results indicate that MRP gene may be important in conferring MDR in gastric and colon cancer cells.

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The hypotensive effect, kinetics, and concentration-response relationship of labetalol, alpha beta- and alpha 1-adrenoceptor blocking drug, were studied in seven women with a moderate-to-severe hypertension (averaged diastolic blood pressure [DBP] of 100 to 120 mm Hg measured during a 1- to 2-day hospitalization period) during the third trimester of pregnancy who received the oral twice-daily doses of 150 to 450 mg. These dosages were individually selected by attaining a therapeutic goal of DBP < or = 100 mm Hg or systolic blood pressure (SBP)/DBP reduction of > 30/15 mm Hg, as compared with the pretreatment value, at any time during the 12-hour dosing interval for a 3- to 5-day dosage escalation period. Labetalol concentrations in plasma were measured by a high-performance liquid chromatography with fluorescence detection, and the plasma drug concentration-response relationship was analyzed by a sigmoidal Emax model. Labetalol decreased significantly (P < 0.05 to 0.01) the pretreatment SBP/DBP (166.3 +/- 5.2/110.3 +/- 3.0 mm Hg, mean +/- SEM) without any recognizable side-effects during the twice-daily dosing period in the mothers. Peaked concentrations occurred at 1 hour postdose in all patients. The elimination half-lives ranged from 4.3 to 6.9 hours, and the apparent oral clearance from 31.9 to 73.3 mL/min/kg. The pharmacodynamic parameters (Emax and EC50) analyzed by the Emax model revealed a 3- to 5-fold interindividual variability. The gestational ages at delivery ranged from 34 to 37 weeks, and the birth weights were < 2000 g in 6 of the 7 neonates. Four neonates developed respiratory distress syndrome after delivery, and one infant died of pulmonary hypoplasia 3 months later. The results indicate that 1) labetalol orally administered in a twice-daily regimen as done in this study is an effective antihypertensive drug in women with hypertension during late pregnancy, and 2) interindividual variability in the kinetic factor (e.g., oral clearance) as well as that in the pharmacodynamic factor (e.g., EC50) appear to be related to the overall variability in the hypotensive responsiveness to the drug. However, whether labetalol and/or hypertension per se would have been related to the fetal outcome remains unanswered from the present study.

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