zaprinast and Lung-Neoplasms

We examined the expression levels of the multidrug resistance protein 5 (ABCC5) gene in non-small cell lung cancer (NSCLC) cell lines to clarify the relationship with the sensitivity to gemcitabine. The expression levels of ABCC5 were inversely correlated with gemcitabine sensitivity significantly (r = 0.628; P < 0.01) in 17 NSCLC cells, whereas the expression of ABCC5 in the gemcitabine-resistant NSCLC cell line H23/GEM-R was the same as that in parental NCI-H23 cells. Treatment with the ABCC5 inhibitor zaprinast altered the sensitivity to gemcitabine in ABCC5-expressing NSCLC cells. In addition, decreasing the expression of ABCC5 by small interfering RNA altered the cytotoxicity to gemcitabine. These results indicate that modulation of ABCC5 activity could be used to increase the gemcitabine sensitivity in NSCLC. Previously, we found a decreased expression of deoxycytidine kinase in H23/GEM-R cells, and further investigation in this study showed an increased expression of ribonucleotide reductase subunit 1 in H23/GEM-R cells. We therefore also examined the effect of modifying the expression of both genes on gemcitabine resistance. We found that using small interfering RNA to decrease the expression of ribonucleotide reductase subunit 1 resulted in a decreased resistance to gemcitabine in H23/GEM-R cells. Furthermore, pretreatment with pemetrexed resulted in an increased deoxycytidine kinase expression concomitant with the alteration of the resistance to gemcitabine in H23/GEM-R cells. The determinants for sensitivity and the acquired resistance in gemcitabine are quite different; nonetheless, modification of these factors may increase the efficacy of gemcitabine in the treatment of NSCLC.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Gene Expression; Glutamates; Guanine; Humans; Lung Neoplasms; Multidrug Resistance-Associated Proteins; Pemetrexed; Phosphodiesterase Inhibitors; Purinones; Ribonucleoside Diphosphate Reductase; RNA, Small Interfering; Tumor Suppressor Proteins

The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram (26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.

Topics: 1-Methyl-3-isobutylxanthine; Adult; Aged; Antihypertensive Agents; Carbachol; Colforsin; Cytosol; Dinoprost; Dose-Response Relationship, Drug; Female; Humans; Isoenzymes; Kinetics; Lung Neoplasms; Male; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle Tonus; Muscle, Smooth, Vascular; Nitroprusside; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Artery; Purinones; Pyridazines; Pyrrolidinones; Rolipram

The effects of the nonselective phosphodiesterase (PDE)-inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors SKF 94120 (type III), rolipram (type IV), zardaverine (type III/IV), and zaprinast (type V) on inherent tone in human airways were investigated. Substantial relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 2.9 microM, n = 14] and SKF 94120 (EC50: 1.4 microM, n = 15); rolipram and zaprinast were almost ineffective. Zardaverine (EC50: 0.31 microM, n = 8), and the combination of SKF 94120 and rolipram (1 microM; EC50: 0.41 microM) were effective relaxants. Biochemical studies revealed the presence of PDE isozymes I, III, IV, and V in the cytosolic and particulate phase of airway homogenates, whereas PDE II was present only in the cytosol. Partial inhibition of total PDE adenosine 3',5'-cyclic monophosphate-hydrolyzing activity was achieved with rolipram and a selective type III inhibitor, whereas there was almost complete inhibition of total PDE activity with either zardaverine or the combination of type III and IV inhibitors. We conclude that all five PDE isozyme families are present in crude preparations of human peripheral airways. Inherent tone in this tissue is most effectively relaxed through selective type III/IV PDE inhibitors.

Topics: 1-Methyl-3-isobutylxanthine; 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adult; Aged; Bucladesine; Colforsin; Dibutyryl Cyclic GMP; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; In Vitro Techniques; Isoenzymes; Lung; Lung Neoplasms; Male; Middle Aged; Muscle Relaxation; Muscle Tonus; Muscle, Smooth; Nitroprusside; Purinones; Pyrazines; Pyridazines; Pyrrolidinones; Rolipram; Vital Capacity