RESUMEN
The cancer chemopreventive agent apigenin also has strong cytostatic and anti-angiogenic effects in vitro. We now investigated its efficacy against experimental Lewis lung carcinomas (LLC), C-6 gliomas and DHDK 12 colonic cancers in vivo. Tumour bearing mice received 50 mg/kg/day apigenin in three different galenical formulations during 12 days in 8-hourly intervals. Only weak effects of apigenin on the size and the number of new tumour blood vessels of both established and newly transplanted tumours were recorded although the intratumoural necrosis was elevated (45 +/- 15% vs. 20 +/- 7% (control), p < 0.05%). These results contrast sharply with the high in vitro sensitivity of LLC, C-6, DHDK 12 and endothelial cells to apigenin where complete growth suppression occurs at concentrations beyond 30 g/ml. Possible causes are discussed.
Asunto(s)
Antineoplásicos/farmacología , Flavonoides/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Apigenina , División Celular/efectos de los fármacos , Flavonoides/administración & dosificación , Flavonoides/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Necrosis , Trasplante de Neoplasias , Ratas , Células Tumorales CultivadasRESUMEN
Gene therapy using herpes simplex type 1 thymidine kinase gene (HSV1-TK) transfer followed by ganciclovir (GCV) treatment has revealed an important intratumoral and regional bystander effect that is at least partly immune-mediated. The aim of this work was to study the modifications of T lymphocyte subpopulations in a model of distant bystander effect occurring between ovary tumors. Bilateral ovarian tumors were generated in 21 WKY rats by injection in the ovarian pouch of either parental or HSV1-TK-expressing DWA-OC-1 ovarian cancer cells. After 14 days, rats were treated for two weeks with GCV (75 mg/kg x 2/d) or saline. All rats were killed at day 29 for pathological examination. The tumor-infiltrating mononuclear cells were analyzed by semi-quantitative immunohistochemistry. As compared to rats receiving saline, GCV-treated animals exhibited a complete disappearance of the HSV1-TK+ tumors with residual fibrotic scars (ovary weights: 0.46 +/- 0.4 g vs 10.11 +/- 1.5 g, P < 0.001). Interestingly, the contralateral HSV1-TK negative tumor showed a significant regression (12.39 +/- 1.93 g vs 22.24 +/- 237 g, P < 0.014). Furthermore, a lower incidence of tumoral ascitis was found in the GCV-receiving group (20% vs 90% P < 0.02). Within both TK- and TK+ tumors, there was a significant increase of CD4+, CD8+ and NK cells in the GCV-treated group compared to the saline-treated group. This study thus indicates that a distant bystander effect not only acts between close tumors within a given organ such as the liver, but also between more distant tumors in the peritoneal cavity. This effect is associated with significant infiltration of the tumor by immune system cells, supporting the notion that the distant bystander effect is immune-mediated.
Asunto(s)
Terapia Genética , Células Asesinas Naturales/patología , Neoplasias Ováricas/terapia , Linfocitos T/patología , Animales , Femenino , Herpesvirus Humano 1/genética , Inmunohistoquímica , Recuento de Linfocitos , Neoplasias Ováricas/patología , Ratas , Ratas Wistar , Timidina Quinasa/genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: This study evaluated the potential of gene therapy against ovarian cancer usin the retroviral transfer of the herpes simplex type 1 thymidine kinase gene (HSV1-TK) followed by ganciclovir treatment. MATERIALS AND METHODS: The sensitivity of 4 different ovarian cancer cell lines (rat ar human) to in vitro infection by recombinant retroviruses were evaluated. Then, their HSV1-TK expressing derivatives were tested for their sensitivity to ganciclovir. One of them, DMBA-OC-1-TK+ was used to generate experimental ovarian cancer in 13 WKY female rats. After 14 days, tl rats received ganciclovir for 12 days (n = 6). The results were expressed in mean +/- ES and were evaluated with the Mann-Whitney test. RESULTS: All cell lines analyzed in this study were sensitive to retroviral mediated gene transfer although with significant variations. The HSV 1-TK expressing derivatives of these cells were 300 7,000-fold more sensitive to ganciclovir, than the parental cells. The ganciclovir dramatically reduced the size of HSV1-TK+ tumors compared to untreated control rats (0 mm3 vs 2,594 mm3, p < 0.001) with complete tumor regression and residual fibrotic scars on pathological examination. Control tumors showed a poorly-differentiated epithelial adenocarcinoma of the ovary. CONCLUSION: In a clinical perspective, the good tolerance and the significant anti-tumoral effects of retroviral-mediated transfer of HSV1-TK gene in animals were encouraging. It remains to set up gene transfer methods that will allow efficient targeting of the ovarian cancer in vivo.
Asunto(s)
Genes Virales , Terapia Genética/métodos , Vectores Genéticos/uso terapéutico , Herpesvirus Humano 1/genética , Modelos Animales , Neoplasias Ováricas/terapia , Timidina Quinasa/genética , Células 3T3 , Animales , Antivirales/uso terapéutico , Femenino , Ganciclovir/uso terapéutico , Humanos , Tolerancia Inmunológica , Ratones , Neoplasias Ováricas/inducido químicamente , Neoplasias Ováricas/inmunología , Ratas , Ratas Wistar , Análisis de Regresión , Timidina Quinasa/administración & dosificaciónRESUMEN
Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, but also between distant tumors. One TKh+ tumor was generated simultaneously with one or multiple TKh- tumors in different rat liver lobes such that there was no contact between the resulting tumors. Both the TKh+ and the TKh- tumors regressed after GCV treatment and showed infiltration with macrophages and T lymphocytes. This distant bystander effect, which is likely immune mediated, should be of major importance for gene therapy of disseminated tumors.