RESUMEN
BACKGROUND: Reolysin is reovirus serotype 3-Dearing strain, a double-stranded replication-competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activated ras pathway due to inhibition of the dsRNA-activated protein kinase. METHODS: This was a single center dose escalation trial of Reolysin administered intravenously every 4 weeks in doses ranging from 1 x 10(8) to 3 x 10(10) tissue culture infective dose (TCID)(50). Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. RESULTS: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a ras G12A mutation. Biopsy from her chest wall mass showed evidence of necrosis and viral replication by electron microscopy. Overall clinical benefit (1 PR + 7 stable disease) rate was 45%, and appeared higher in patients with viral shedding (67%) than those without (33%). CONCLUSION: Reolysin administered monthly as a one-hour infusion is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies.
Asunto(s)
Antineoplásicos/administración & dosificación , Orthoreovirus Mamífero 3/fisiología , Neoplasias/terapia , Replicación Viral/fisiología , Adulto , Anciano , Formación de Anticuerpos/inmunología , Antineoplásicos/efectos adversos , Análisis Mutacional de ADN , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Orthoreovirus Mamífero 3/ultraestructura , Persona de Mediana Edad , Mutación/genética , Neoplasias/inmunología , ARN Viral/sangre , ARN Viral/orinaRESUMEN
BACKGROUND: Vulnerable plaque demonstrates intense inflammation in which macrophages secrete matrix metalloproteinases (MMPs) that degrade the fibrous cap, ultimately leading to rupture, in situ thrombosis, and an associated clinical event. Thus, inhibition of MMP activity or more general suppression of vascular inflammation are attractive targets for interventions intended to reduce plaque rupture. We hypothesized that subantimicrobial doses of doxycycline (SDD) (20 mg twice daily) would benefit patients with coronary artery disease by reducing inflammation and MMP activity and thus possibly prevent coronary plaque rupture events. METHODS AND RESULTS: We conducted a prospective, randomized, double-blind, placebo-controlled pilot study of 6 months of SDD or placebo treatment to reduce inflammation and prevent plaque rupture events. A total of 50 patients were enrolled, of whom 24 were randomized to placebo and 26 to SDD. At 6 months, there was no difference in the composite endpoint of sudden death, fatal myocardial infarction (MI), non-fatal MI, or troponin-positive unstable angina in SDD compared with placebo-treated patients (8.4% versus 0%, P=0.491). Biochemical markers of inflammation were assessed in plasma at study entry and after 6 months of therapy in 30 patients. In SDD-treated patients, high-sensitivity C-reactive protein (CRP) was reduced by 46% from 4.8+/-0.6 microg/mL to 2.6+/-0.4 microg/mL (P=0.007), whereas CRP was not significantly reduced in placebo patients. Interleukin (IL)-6 decreased from 22.1+/-3.7 pg/mL at baseline to 14.7+/-1.8 pg/mL at 6 months in SDD-treated patients (P=0.025) but did not decrease significantly in placebo-treated patients. On zymography, pro-MMP-9 activity was reduced 50% by SDD therapy (P=0.011), whereas it was unchanged by placebo treatment. CONCLUSIONS: SDD appears to exert potentially beneficial effects on inflammation that could promote plaque stability. These findings should be investigated in a larger study.