RESUMEN
Preclinical evaluation of candidate human immunodeficiency virus (HIV) vaccines entails challenge studies whereby non-human primates such as macaques are vaccinated with either an active or control vaccine and then challenged (exposed) with a simian-version of HIV. Repeated low-dose challenge (RLC) studies in which each macaque is challenged multiple times (either until infection or some maximum number of challenges is reached) are becoming more common in an effort to mimic natural exposure to HIV in humans. Statistical methods typically employed for the testing for a vaccine effect in RLC studies include a modified version of Fisher's exact test as well as large sample approaches such as the usual log-rank test. Unfortunately, these methods are not guaranteed to provide a valid test for the effect of vaccination. On the other hand, valid tests for vaccine effect such as the exact log-rank test may not be easy to implement using software available to many researchers. This paper details which statistical approaches are appropriate for the analysis of RLC studies, and how to implement these methods easily in SAS or R.
Asunto(s)
Relación Dosis-Respuesta a Droga , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Simulación por Computador , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Macaca mulatta , Método de Montecarlo , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacosRESUMEN
Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment.