RESUMO
Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol-succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R.
Assuntos
Antineoplásicos/farmacologia , Bombesina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Toxinas Marinhas/farmacologia , Oligopeptídeos/farmacologia , Células 3T3 , Animais , Antineoplásicos/química , Bombesina/química , Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citosol/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Toxinas Marinhas/química , Camundongos , Pró-Fármacos/farmacologia , Ligação Proteica , Receptores de Droga/efeitos dos fármacosRESUMO
The mechanism by which vasoactive intestinal peptide (VIP)-ellipticine (E) conjugates are cytotoxic for human lung cancer cells was investigated. VIP-alanyl-leucyl-alanyl-leucyl-alanine (ALALA)-E and VIP-leucyl-alanyl-leucyl-alanine (LALA)-E inhibited (125)I-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 microM, respectively. VIP-ALALA-E and VIP-LALA-E caused elevation of cAMP in NCI-H1299 cells with ED50 values of 0.7 and 0.1 microM. Radiolabeled VIP-LALA-E was internalized at 37 degrees C and delivered the cytotoxic E into NCI-H1299 cells. VIP-LALA-E inhibited the growth of NCI-H1299 cells in vitro. Three days after the addition of VIP-LALA-E to NCI-H1299 cells, cell viability decreased based on trypan blue exclusion and reduced 3H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC1 receptor-mediated endocytosis.
Assuntos
Antineoplásicos/síntese química , Elipticinas/síntese química , Peptídeo Intestinal Vasoativo/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/biossíntese , Desenho de Fármacos , Elipticinas/química , Elipticinas/farmacocinética , Elipticinas/farmacologia , Endocitose , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptores de Peptídeo Intestinal Vasoativo/agonistas , Receptores de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo , Timidina/metabolismo , Peptídeo Intestinal Vasoativo/química , Peptídeo Intestinal Vasoativo/farmacocinética , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
CAPROSYN* suture is the latest innovation in monofilament synthetic suture. This suture is prepared from POLYGLYTONE*6211, a synthetic polyester composed of glycolide, caprolactone, trimethylene carbonate, and lactide. The purpose of this study was to compare the biomechanical performance of CAPROSYN* suture to that of CHROMIC GUT suture. The biomechanical performance studies included quantitative measurements of wound security, strength loss, mass loss, potentiation of infection, tissue drag, knot security, knot rundown, as well as suture stiffness. Both CAPROSYN* and CHROMIC GUT sutures provided comparable resistance to wound disruption. Prior to implantation, suture loops of CAPROSYN* had a significantly greater mean breaking strength than suture loops of CHROMIC GUT. Three weeks after implantation of these absorbable suture loops, the sutures had no appreciable strength. The rate of loss of suture mass of these two sutures was similar. As expected, CHROMIC GUT sutures potentiated significantly more infection than did the CAPROSYN* sutures. The handling properties of the CAPROSYN* sutures were far superior to those of the CHROMIC GUT sutures. The smooth surface of the CAPROSYN* sutures encountered lower drag forces than did the CHROMIC GUT sutures. Furthermore, it was much easier to reposition the CAPROSYN* knotted sutures than the knotted CHROMIC GUT sutures. In the case of CHROMIC GUT sutures, it was not possible to reposition a two-throw granny knot. These biomechanical performance studies demonstrated the superior performance of synthetic CAPROSYN* sutures compared to CHROMIC GUT sutures and provide compelling evidence of why CAPROSYN* sutures are an excellent alternative to CHROMIC GUT sutures.
Assuntos
Implantes Absorvíveis , Poliésteres/síntese química , Suturas , Animais , Fenômenos Biomecânicos , Dioxanos , Feminino , Agulhas , Polímeros , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.