RESUMO
Replication competent oncolytic herpes simplex viruses (HSV) with broad-spectrum activity against various cancers, including prostate cancer, exert a dual effect by their direct cytocidal action and by eliciting tumor-specific immunity. These viruses can deliver immunoregulatory molecules to tumors so as to enhance the cumulative antitumor response. This is particularly desirable for prostate cancers, which are usually poorly immunogenic. Initial studies described herein comparing the efficacy of three different oncolytic HSVs (G207, G47Delta, and NV1023) to inhibit the growth of the poorly immunogenic TRAMP-C2 mouse prostate tumors demonstrated that NV1023 was most effective in treating established tumors. The expression of IL-12 on an NV1023 background (NV1042), but not the expression of GM-CSF (NV1034), further enhanced the efficacy of NV1023 in two murine prostate cancer models with highly variable MHC class I levels, Pr14-2 with 91% and TRAMP-C2 with 2% of cells staining. NV1042 also inhibited the growth of distant noninoculated tumors in both prostate cancer models. NV1042 treated tumors exhibited increased immune cell infiltration and decreased levels of angiogenesis. Thus, an IL-12 expressing oncolytic herpes virus, which is capable of direct cytotoxicity and can modulate the otherwise suboptimal immune response through concomitant expression of the cytokine at the site of tumor destruction, could serve as a valuable clinical agent to seek out both overt and occult prostate cancers.
Assuntos
Terapia Genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Herpesvirus Humano 1/imunologia , Interleucina-12/uso terapêutico , Terapia Viral Oncolítica , Neoplasias da Próstata/terapia , Simplexvirus/genética , Animais , Terapia Combinada , Genes MHC Classe I/fisiologia , Vetores Genéticos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Herpesvirus Humano 1/genética , Humanos , Interferon gama/farmacologia , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vírus Oncolíticos/patogenicidade , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Replicação ViralRESUMO
One hundred and fifty males in the age group 10-17 years were studied longitudinally for 2 years to determine their physical and pubertal development. The velocity of linear growth, weight gain and pubertal growth velocities were determined. The relation between peak height velocity and genital stages and between genital stages and pubic hair was determined. It is concluded from this study that 86 percent of normal males reach peak height velocity while in G4 and only 5% will not have achieved peak height velocity by the time G5 is reached.
