RESUMEN
N-4,5-Di-(4-dialkylamino)phenyl imidazoles (A) are potent modulators of P-glycoprotein mediated multidrug resistance. This manuscript describes the discovery and lead optimization of this novel class of inhibitors.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Imidazoles/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiologíaRESUMEN
Solution-phase combinatorial chemistry was applied to the optimization and development of clinical candidate OC144-093 (22), a novel and nontoxic modulator of P-glycoprotein mediated multidrug resistance.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Imidazoles/farmacología , Técnicas Químicas Combinatorias , Semivida , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Masculino , Estructura Molecular , Valores de ReferenciaRESUMEN
OC144-093 is a novel substituted diarylimidazole (Mr 495) generated using the OntoBLOCK system, a solid-phase combinatorial chemistry technology, in combination with high-throughput cell-based screening. OC144-093 reversed multidrug resistance (MDR) to doxorubicin, paclitaxel, and vinblastine in human lymphoma, breast, ovarian, uterine, and colorectal carcinoma cell lines expressing P-glycoprotein (P-gp) with an average EC50 of 0.032 microM. Inhibition of MDR by OC144-093 was reversible, but the effect persisted for at least 12 h after removal of compound from the culture medium. OC144-093 had no effect on the response to cytotoxic agents by cells in vitro lacking P-gp expression or expressing a multidrug resistance-associated protein (MRP-1). OC144-093 was not cytotoxic by itself against 15 normal, nontransformed, or tumor cell lines, regardless of P-gp status, with an average cytostatic IC50 of >60 microM. OC144-093 blocked the binding of [3H]azidopine to P-gp and inhibited P-gp ATPase activity. The compound was >50% p.o. bioavailable in rodents and dogs and did not alter the plasma pharmacokinetics of i.v.-administered paclitaxel. OC144-093 increased the life span of doxorubicin-treated mice engrafted with MDR P388 leukemia cells by >100% and significantly enhanced the in vivo antitumor activity of paclitaxel in MDR human breast and colon carcinoma xenograft models, without a significant increase in doxorubicin or paclitaxel toxicity. The results demonstrate that OC144-093 is an orally active, potent, and nontoxic inhibitor of P-gp-mediated multidrug resistance that exhibits all of the desired properties for treatment of P-gp-mediated MDR, as well as for prevention of MDR prior to selection and/or induction of refractory disease.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Múltiples Medicamentos , Imidazoles/farmacología , Adenosina Trifosfatasas/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/farmacología , División Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Imidazoles/química , Concentración 50 Inhibidora , Cinética , Ratones , Ratones SCID , Paclitaxel/farmacología , Ratas , Factores de Tiempo , Células Tumorales Cultivadas , Vinblastina/farmacologíaRESUMEN
PURPOSE: We investigated the relationship between the basal and treatment-induced change in the tumor expression of the drug resistance gene MDR1 and the cellular injury response gene GADD153, and clinical response to paclitaxel treatment. METHODS: MDR1 and GADD153 mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) in tumor samples obtained by fine needle aspiration biopsy from 14 patients before and 24 h after paclitaxel infusion. RESULTS: There was no difference between responders and non-responders with respect to either the basal MDR1 mRNA level or the change in MDR1 mRNA level at 24 h after treatment (P = 0.464). Likewise, there was no difference in basal GADD153 mRNA level between responders and non-responders. However, there was a significantly greater increase in GADD153 mRNA at 24 h in responders compared with non-responders (P = 0.005). An increase in GADD153 mRNA level of 1.5-fold or higher predicted response with a sensitivity of 86% and a specificity of 100%. CONCLUSIONS: An increase in GADD153 mRNA level reflects chemotherapy-induced damage sufficient to be manifest as a clinically detectable reduction in tumor volume. Measurement of the change in GADD153 mRNA level successfully identified patients destined to respond as early as 24 h post-treatment.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Proteínas Potenciadoras de Unión a CCAAT , Proteínas de Unión al ADN/genética , Neoplasias/tratamiento farmacológico , Paclitaxel/uso terapéutico , ARN Mensajero/análisis , Factores de Transcripción/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Femenino , Humanos , Neoplasias/metabolismo , Paclitaxel/farmacología , Factor de Transcripción CHOP , Células Tumorales CultivadasRESUMEN
Cells injured by exposure to cisplatin (cDDP) undergo a cellular injury response that shares characteristics with responses produced by many other injurious agents. We sought to determine whether the increase of the message of the "growth arrest and DNA damage-inducible" gene, GADD153, could be used to assess the extent of the cellular injury response in model systems and in patients with head and neck cancer after treatment with cDDP. The mRNA levels of GADD153, a gene highly transcriptionally activated by cDDP damage, were increased in a transient, concentration-dependent manner by cDDP when human UMSCC10b head and neck carcinoma cells were treated with cDDP both in vitro and when grown as tumor xenografts in nude mice. There was a good correlation between the change in level of GADD153 mRNA and UMSCC10b cell kill by cDDP in vitro (r = 0.98). The magnitude of the increase was proportionally reduced in UMSCC10b sublines that were 3- or 6-fold resistant to cDDP. GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer. There was a relationship between the increase in GADD153 mRNA levels and the response rate. Seven of the 32 patients had no response and no increase in GADD153 mRNA level. Among the eight patients who attained a partial response, the increase in GADD153 message ranged from 0.7-2.5-fold. In contrast, 17 of 32 patients had a complete response, and this was accompanied by a 2-9-fold induction of GADD153. The mean increase in the complete responders (3.8+/-2.2-fold) differed significantly from that for the partial responders (1.6+/-0.9) and nonresponders (0.8+/-0.5; P <0.05); the difference between the partial responders and nonresponders was also significant (P <0.05). An increase of GADD153 mRNA of 1.75-fold or higher predicted a complete response, with a sensitivity of 94% and a specificity of 87%. We conclude that the magnitude of the increase in GADD153 mRNA is a promising candidate for service as an intermediate marker of head and neck tumor response to cDDP. The fact that the change in GADD153 mRNA reflects the actual extent of injury sustained by the tumor makes it particularly attractive as a potential marker. One strength of this approach is that it can provide a measure of the effectiveness of therapy as early as 24-48 h after the first dose of treatment.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Proteínas de Unión al ADN/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Factores de Transcripción/metabolismo , Animales , Antineoplásicos/uso terapéutico , Biomarcadores , Cisplatino/uso terapéutico , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Evaluación de Resultado en la Atención de Salud/métodos , Reacción en Cadena de la Polimerasa , Control de Calidad , ARN Mensajero/metabolismo , Factor de Transcripción CHOP , Factores de Transcripción/genética , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Lung cancer is now the number one cause of cancer death for both men and women. An age-adjusted analysis over the past 25 years shows that in women specifically, lung cancer incidence is on the rise. It is estimated that 10-20 genetic events including the alteration of oncogenes and tumor suppressor genes will have occurred by the time a lung tumor becomes clinically evident. In an effort to identify regions containing novel cancer genes, chromosome 18p11, a band not previously implicated in disease, was examined for loss of heterozygosity (LOH). In this study, 50 matched normal and NSCLC tumor samples were examined using six 18p11 and one 18q12.3 PCR-based polymorphic markers. In addition, LOH was examined in 29 glioblastoma pairs and 14 paired breast carcinomas. This analysis has revealed potentially two regions of LOH in 18p11 in up to 38% of the tumor samples examined. The regions of LOH identified included a 2 cm area between markers D18S59 and D18S476, and a more proximal, 25 cm region of intermediate frequency between D18S452 and D18S453. These results provide evidence for the presence of one or more potential tumor suppressor genes on the short arm of chromosome 18 which may be involved in NSCLC, brain tumors and possibly breast carcinomas as well.