Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans.

PURPOSE: The overexpression of c-myc associated with uncontrolled cell proliferation is a frequent genetic event in androgen-refractory prostatic neoplasia. The purpose of this study was to evaluate the bioavailability and efficacy of a novel antisense phosphorodiamidate morpholino oligomer directed against c-myc, AVI-4126, in PC-3 androgen-independent human prostate cancer xenograft murine model and its safety in a Phase I human clinical study. EXPERIMENTAL DESIGN: AVI-4126 administration in athymic mice bearing s.c. PC-3 xenografts was carried out to determine the bioavailability, tolerance, antitumor activity, and histological changes induced by targeted inhibition of c-Myc expression using a specific morpholine antisense oligomer. The Phase I safety study involved a single center, open label, dose-escalating design in healthy volunteers after i.v. administration of AVI-4126. RESULTS: The data reveal that AVI-4126 targets and inhibits c-myc translation in a sequence-specific manner and causes significant growth inhibition and apoptosis in prostate cancer cells and in s.c. tumor xenografts. A 75-80% reduction in tumor burden was observed in AVI-4126-treated animals compared with the scrambled oligomer and saline control groups. Histologically, tumors grown in the athymic mice treated with AVI-4126 were less cellular and vascular than those in control mice and showed an increased level of cellular degeneration, cytoplasmic vacuoles, and hyperchromatic nuclei. Phase I safety trials in humans via i.v. route of administration showed no toxicity or serious adverse events. CONCLUSIONS: The present study demonstrates that inhibition of c-Myc expression by antisense phosphorodiamidate morpholino oligomer is a promising new and safe therapeutic strategy for prostate cancer.

Reanalysis of carbamazepine and carbamazepine-epoxide pharmacokinetics after multiple dosing of extended release formulation.

PURPOSE: To model and re-evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10, 11-epoxide (CBZ-E) after 5 day b.i.d. dosing with either Carbatrol (extended-release beads) or Tegretol-XR (an osmotic pump tablet, an Oros tablet) using compartmental method. METHODS: Plasma concentration time profile data from 15 normal healthy adults received, in a randomized crossover fashion, Carbatrol (2 x 200 mg capsules), b.i.d. for 5 days and Tegretol-XR (400 mg), b.i.d. for 5 days were available for analysis from previous study. The compartmental kinetic parameters of CBZ and CBZ-E were simultaneously fitted by assuming: i) one compartment open model with zero order absorption with lag time, and first order elimination for CBZ and ii) one compartment open model with Michaelis-Menten formation with a sigmoidity factor, and first order elimination for CBZ-E. Time to 50% of CBZ plateau concentrations (TC50) was estimated and statistically compared between the two products. RESULTS: There was a good agreement between simulated and observed plasma concentrations. For CBZ, the fitted parameters were: the first order elimination rate constant (K(10)) 0.024 and 0.022 hr(-1), t(1/2) 27.3 and 30.3 hr, volume of central compartment (V(1) ) 1.119 and 1.160 L/kg, for Carbatrol and Tegretol-XR, respectively. For CBZ-E, the fitted parameters were: the first order elimination rate constant (K (30) ) 0.128 and 0.157 hr (-1), t (1/2) 6.1 and 5.1 hr, volume of central compartment (V (3) ) 0.728 and 0.644 L/kg, V (max) 0.085 and 0.076 mg/hr/kg, K (m) 28.639 and 33.138 mg/mL, for Carbatrol and Tegretol-XR, respectively. The fitted pharmacokinetic parameters of CBZ and CBZ-E were generally consistent with published values from previous studies. A minimal rise in CBZ-E concentrations was observed during the first 12 hours, the finding of which has not been reported before. Consequently, the CBZ-E plasma profiles appear as sigmoid curves and have a different shape compared to those of the CBZ profiles. The inclusion of the sigmoidity factor allowed flexibility in the fitting and optimized the simulation results. When compared to published literature of single dose data, the investigation of CBZ and CBZ-E pharmacokinetics from this study suggested that autoinduction might occur by the fifth day of dosing and might partly contribute to the sigmoidal shape of CBZ-E profiles. CONCLUSION: The fitted model well described the plasma profiles of both CBZ and CBZ-E. Carbatrol and Tegretol-XR were similar in their pharmacokinetics based on compartmental analysis.

Active specific immunotherapy with a beta-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival.

PURPOSE: Human chorionic gonadotropin (hCG) is produced by colorectalcancers and may play a role in its progression. The clinical and immunological effects of a synthetic vaccine targeting beta-hCG composed of the COOH terminal peptide of beta-hCG (CTP37) conjugated to diphtheria toxoid (DT) was investigated in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: Seventy-seven patients from 12 centers were randomly divided into two vaccine dose groups. CTP37-DT was formulated in an emulsion and administered i.m. on days 0, 28, and 70. Patients were evaluated for toxicity, overall survival, and antibody response to hCG and to DT. RESULTS: Immunizations were well tolerated with no patients requiring cessation of the injections. Anti-hCG antibody was detected in 56 of the 77 patients treated. Significant differences in antibody response and survival were not observed between the two dose groups. An intention-to-treat analysis of all vaccinated patients showed a median survival of 34 weeks. Patients who developed anti-hCG antibody levels higher than or equal to the median value exhibited a median survival of 45 weeks compared with 24 weeks for patients who developed anti-hCG antibody levels lower than the median (P = 0.0002). In contrast, no significant difference was observed when comparing survival based upon the level of DT antibody that developed (P = 0.80). CONCLUSIONS: Vaccination with CTP37-DT induced anti-hCG antibodies in most patients with advanced colorectal cancer. Anti-hCG antibody induction was associated with longer overall survival. CTP37-DT has an excellent safety profile and warrants further study in patients with colorectal cancer.