Elevated tumor cyclooxygenase (COX)-2 activity plays a multifaceted role in non-small cell lung cancer (NSCLC). To elucidate the role of COX-2 in the in vitro and in vivo expression of two known NSCLC angiogenic peptides, CXC ligand (CXCL) 8 and CXCL5, we studied two COX-2 gene-modified NSCLC cell lines, A549 and H157. COX-2 overexpression enhanced the in vitro expression of both CXCL8 and CXCL5. In contrast, specific COX-2 inhibition decreased the production of both peptides as well as nuclear translocation of nuclear factor B. In a severe combined immunodeficient mouse model of human NSCLC, the enhanced tumor growth of COX-2-overexpressing tumors was inhibited by neutralizing anti-CXCL5 and anti-CXCL8 antisera. We conclude that COX-2 contributes to the progression of NSCLC tumorigenesis by enhancing the expression of angiogenic chemokines CXCL8 and CXCL5.

ABSTRACT

The influence of the CCK-A antagonist devazepide and the CCK-B/gastrin antagonist L-365,260 on the locomotor activity of mice was studied. Devazepide and L-365,260 had opposite effects on spontaneous locomotor activity, and on caerulein- and apomorphine-induced hypomotility in the mouse. Devazepide in high doses (0.1-1 mg/kg IP) reduced spontaneous motor activity, whereas L-365,260 at a high dose (1 mg/kg IP) increased the activity of mice. Devazepide (0.1-10 micrograms/kg) moderately antagonized the sedative effect of apomorphine (0.1 mg/kg SC) and caerulein (25 micrograms/kg SC), whereas L-365,260 (1-10 micrograms/kg) significantly potentiated the actions of dopamine and CCK agonists. Concomitant administration of caerulein (15 micrograms/kg SC) and apomorphine (0.1 mg/kg SC) caused an almost complete loss of locomotor activity in the mouse. Devazepide and L-365,260 (0.1-10 micrograms/kg) were completely ineffective against caerulein-induced potentiation of apomorphine hypomotility. Devazepide in high doses (0.1-1 mg/kg), reducing the spontaneous motor activity of mice, counteracted the motor excitation induced by d-amphetamine (5 mg/kg IP). The CCK agonist caerulein (100 micrograms/kg SC) had a similar antiamphetamine effect. Devazepide (1-100 micrograms/kg) and L-365,260 (1 micrograms/kg) reversed completely the antiamphetamine effect of caerulein. The results of present study reflect apparently distinct role of CCK-A and CCK-B receptors in the regulation of motor activity. The opposite effect of devazepide and L-365,260 on caerulein- and apomorphine-induced hypolocomotion is probably related to the antagonistic role of CCK-A and CCK-B receptor subtypes in the regulation of mesencephalic dopaminergic neurons. The antiamphetamine effect of caerulein is possibly linked to the stimulation of CCK-A receptors in the mouse brain, whereas the blockade of both subtypes of the CCK-8 receptor is involved in the antiamphetamine effect of devazepide.

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