RESUMEN
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacología , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Ratones , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Profármacos/síntesis química , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Camptotecina/sangre , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacocinética , ADN-Topoisomerasas de Tipo I/metabolismo , Perros , Haplorrinos , Humanos , Concentración de Iones de Hidrógeno , Irinotecán , Ratones , Ratones Desnudos , Profármacos/química , Profármacos/farmacocinética , Ratas , Inhibidores de Topoisomerasa I , Trasplante Heterólogo , Agua/químicaRESUMEN
PURPOSE: Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11). METHODS: A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs. RESULTS: A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED(50)) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab. CONCLUSION: It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/biosíntesis , Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Dipéptidos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Proteínas de Neoplasias/biosíntesis , Profármacos/uso terapéutico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Acetilcolinesterasa/metabolismo , Animales , Antineoplásicos/farmacología , Camptotecina/farmacología , Camptotecina/uso terapéutico , Línea Celular Tumoral , Dipéptidos/farmacología , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Irinotecán , Masculino , Ratones , Ratones Desnudos , Profármacos/farmacología , Solubilidad , Agua , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.