RESUMO
PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 h that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 h in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Caspase 3/metabolismo , Ativadores de Enzimas/farmacocinética , Saúde , Hidrazonas/farmacocinética , Piperazinas/farmacocinética , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacocinética , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Extratos Celulares , Linhagem Celular Tumoral , Cães , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/efeitos adversos , Ativadores de Enzimas/farmacologia , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/efeitos adversos , Hidrazonas/farmacologia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/farmacologia , Bibliotecas de Moléculas Pequenas/efeitos adversos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de TempoRESUMO
A 7 yr old castrated male standard poodle weighing 25 kg was presented with a 5 day history of hematuria, dysuria, and the presence of a 2.5 cm, firm swelling within the prepuce. Abdominal radiographs revealed a soft-tissue mass on the distal prepuce and lysis of the cranial margin of the os penis. The patient was sedated and an ulcerated hemorrhagic mass was identified at the tip of the penis. The mass was diagnosed as hemangiosarcoma via incisional biopsy. A penile amputation with scrotal urethrostomy was performed followed by chemotherapy with doxorubicin.
Assuntos
Antineoplásicos/uso terapêutico , Doenças do Cão/cirurgia , Hemangiossarcoma/veterinária , Neoplasias Penianas/veterinária , Pênis/cirurgia , Escroto/cirurgia , Amputação Cirúrgica/veterinária , Animais , Doenças do Cão/tratamento farmacológico , Cães , Hemangiossarcoma/tratamento farmacológico , Hemangiossarcoma/cirurgia , Masculino , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/cirurgia , Pênis/patologiaRESUMO
A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase autoactivating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted s.c. as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous i.v. infusion of S-PAC-1 in dogs led to a steady-state plasma concentration of â¼10 µmol/L for 24 to 72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well tolerated and that the treatments induced partial tumor regression or stable disease in four of six subjects. Our results support this canine setting for further evaluation of small-molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic.