Inhibitory Effect Of Combined Treatment Research Articles

Serum-stimulated α1type IV collagen gene transcription is mediated by TGF-β and inhibited by estradiol

We examined the hypothesis that fetal calf serum (FCS) stimulates murine mesangial cell alpha 1 type IV collagen (COL4A1) gene transcription by increasing autocrine production of transforming growth factor-beta (TGF-beta) through a platelet-derived growth factor (PDGF)-dependent mechanisms. PDGF-stimulated COL4A1 gene transcription was inhibited by neutralizing antibody to TGF-beta (119.3 +/- 3.6 vs. 106.0 +/- 6.2 relative luciferase units, expressed as a percentage of control untreated cells, P < 0.003). FCS-stimulated gene transcription was inhibited by neutralizing antibody to PDGF (148.3 +/- 4.1 vs. 136.7 +/- 0.3 relative luciferase units, P < 0.002) and by neutralizing antibody to TGF-beta (148.3 +/- 4.1 vs. 127.1 +/- 3.4 relative luciferase units, P < 0.036). The inhibitory effect of combined treatment with anti-PDGF and anti-TGF-beta antibody on gene transcription was no greater than that of anti-TGF-beta antibody alone [129.5 +/- 0.53 vs. 127.1 +/- 3.4 relative luciferase units, P = not significant (NS)]. FCS-stimulated gene transcription was also inhibited by estradiol (10(-7) M) (148.4 +/- 3.1 vs. 119.4 +/- 8.1 relative luciferase units, P < 0.019). In the presence of estradiol, anti-TGF-beta antibody failed to further reduce serum-stimulated gene transcription (119.4 +/- 8.1 vs. 115.6 +/- 9.8, P = NS), suggesting that estradiol reverses FCS-stimulated COL4A1 gene transcription by antagonizing the actions of TGF-beta. Measurement of type IV collagen synthesis by Western blotting confirmed that the intact gene responded in a manner analogous to the promoter construct.

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The apperance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.

Vasoinhibitory effect of NP-252, a new dihydropyridine derivative, in canine cerebral artery

The vasoinhibitory effect of NP-252, a 1,4-dihydropyridine derivative Ca ++ antagonist, was examined in canine cerebral artery, and this effect was compared with that of nifedipine. NP-252 (10 −7 M) and nifedipine (10 −6 M) nearly abolished the contraction induced by addition of Ca ++ to Ca ++-free medium containing KCl. NP-252 (10 −6 M) and nifedipine (10 −6 M) attenuated the contraction produced by thromboxane A 2 agonist (STA 2) in normal medium, and the resultant contractions were 22% (n = 6) and 35% (n = 6) of the control contraction, respectively. The vasoinhibitory effects of NP-252 were significantly stronger than those of nifedipine in canine cerebral artery. NP-252 (10 −7 and 10 −6 M) dose-dependently attenuated nifedipine-resistant Ca ++-contraction in the presence of STA 2 in both canine cerebral and coronary arteries. The inhibitory effect of combined treatment with NP-252 (10 −6 M) and nitroglycerin (10 −6 M) on nifedipine-resistant Ca ++-contraction in the cerebral artery was additive. These results indicate that NP-252 possesses a stronger vasoinhibitory effect than that of nifedipine in canine cerebral artery.

Growth inhibitory effects of combined treatment with levamisole and 5-FU on human colorectal adenocarcinoma grafted in nude mice : Van Ginckel R., Distelmans W. ∗, De Brabander M., Callens M., Janssens B., Jagers E. and De Coster R., Janssen Research Foundation, B-2340 Beerse, Belgium; ∗Free University Brussels, Academic Hospital, B-1090 Jette, Belgium

Growth inhibitory effects of combined treatment with levamisole and 5-FU on human colorectal adenocarcinoma grafted in nude mice : Van Ginckel R., Distelmans W. ∗, De Brabander M., Callens M., Janssens B., Jagers E. and De Coster R., Janssen Research Foundation, B-2340 Beerse, Belgium; ∗Free University Brussels, Academic Hospital, B-1090 Jette, Belgium