Transfer of a herpes simplex virus-derived thymidine kinase (HSV-tk) gene into brain tumor cells and subsequent ganciclovir (GCV) treatment has been shown by others to be an effective treatment in rats with intracerebrally inoculated 9L gliosarcomas. Mechanism of action and reproducibility are, however, still a matter of debate. We have used the same model to test the therapeutic effects of both retrovirus- and adenovirus-mediated transfer of the HSV-tk gene followed by GCV treatment. Survival time of rats with intracerebral 9L tumors was significantly prolonged after a single administration of adenovirus carrying a HSV-tk gene as compared to controls. Retrovirus-mediated gene transfer also resulted in significantly prolonged survival time when recombinant retrovirus-producing cells were transplanted. Direct injection of the recombinant retrovirus, HSV-tk-expressing cells, virus-producing cells without GCV administration and recombinant retrovirus-lacZ or interleukin-2 (IL-2)-producing cells did not result in tumor cell kill. In the present study, no significant difference in survival of 9L brain tumor carrying rats was found after treatment with adenovirus as compared to retrovirus-mediated HSV-tk-mediated gene transfer and subsequent GCV treatment.
Replication-defective adenovirus vectors were generated inoculated on day 0 with 10 5 II-45 cells into the pleural in which the gene of interest (lacZ, luciferase or HSV-tk) is cavity, received 7 × 10 9 infectious particles of IG.Ad. driven by the adenovirus major late promoter (MLP) or CMV.TK on day 1, day 2, day 4 or day 8. One day after the human cytomegalovirus immediate-early gene virus administration, 25 mg/kg GCV or PBS (controls) was promoter/enhancer (CMV). In vitro experiments with rat (IIinjected i.p. (intraperitoneally) twice daily. On day 15, all 45) and human (MERO 25) mesothelioma cell lines animals were killed. Significant tumor regression, equivalrevealed that the CMV promoter was stronger than the ent to 5 log cell kill, occurred in the treated rats suggesting MLP promoter regarding levels of expression of the luciferan impressive bystander effect. In a survival study, animals ase reporter gene and ganciclovir (GCV) killing efficiency were treated 9 days after inoculation of 10 5 tumor cells with after tk gene transfer. Following administration of IG.Ad.CMV.TK and a 14 days course of GCV. This treat-IG.Ad.CMV.lacZ recombinant adenovirus (Introgene, IG) ment prolonged symptom-free survival time from 19 days into the pleural cavity of Fischer rats with established in the controls to 33 days in the treated group. These mesothelioma, a widespread distribution of infectious virus responses can be best explained by assuming continued particles through the thorax contents was demonstrated.tk expression in or around the tumor tissue during GCV However, a relatively small proportion of tumor cells were treatment. Our results confirm and extend earlier findings transduced. Nevertheless, a strong tumor growth inhibition with the same model and demonstrate the potential of the was observed following treatment with IG.Ad.CMV.TK herpes simplex virus thymidine kinase suicide gene recombinant adenovirus and GCV. Separate groups of rats therapy as a local treatment for malignant mesothelioma.
Cytokine gene therapy was studied in established L42 tumour responses. These were due to local release of cytotumours in syngeneic rats. L42 is a transplantable nonkines, not to systemic effects. Growth retardation also immunogenic non-small cell lung cancer (NSCLC). Genes occurred in contralateral tumours which were not injected. coding for human interleukin-1␣ and for rat interleukin-3When rats carrying established tumours were vaccinated were transferred by injecting producer cells of recombinant with lysates of tumours collected during treatment with adenovirus vectors into the tumour in attempts to achieve 'cracked' producer cells, significant tumour growth retarhigh concentrations of the cytokines inside the tumor withdation was obtained. We speculate that both cytokines, if out systemic toxicity. Limited tumour growth delay was produced at sufficiently high concentrations in tumours, obtained with viable producer cells. For logistic reasons induce inflammation which in turn initiates an immune stocks of pooled frozen producer cells allowed intensive response against tumours growing at a distant site. These treatment of groups of tumour bearing rats. The cells were findings seem to justify further exploration of IL-1 and IL-3 lysed by thawing before administration. Ten daily injections gene transfer for the treatment of cancers. of such 'cracked' producer cells induced reproducible
The authors constructed recombinant adenoviral vectors to investigate their potential for gene therapy treatment of leptomeningeal metastases. Several human cell lines that were derived from tumors occurring as leptomeningeal metastases and that were infected in vitro with major late promoter recombinant adenovirus containing the luciferase (luc) gene (IG.Ad.MLP.luc) showed high levels of expression. When these human tumor cell lines were infected in vitro with recombinant adenovirus harboring the herpes simplex virus-thymidine kinase (HSV-tk) gene (IG.Ad.MLP.TK), they were highly sensitive to the killing effects of ganciclovir (GCV). Transduction efficiency of leptomeningeal tumor cells in vivo was assessed by injecting 9-L rat brain tumor cells into the cerebrospinal fluid of Fischer rats via the cisterna magna. After 3 days, recombinant adenovirus containing the lacZ reporter gene (IG.Ad.MLP.lacZ) was injected via the same route. Six days after tumor cell injection, expression of the reporter gene was observed in tumor cells along the total neural axis. Subsequently, rats with leptomeningeal metastases were treated 3 days after tumor cell injection with HSV-tk. Beginning on the next day, GCV was injected intraperitoneally for 10 days. The rats that developed neurological symptoms were killed immediately. The symptom-free latency of every rat was determined. The rats treated with HSV-tk and subsequent GCV had significantly longer (p < 0.01) symptom-free latency than all control groups. This study demonstrates the feasibility and efficacy of this therapeutic approach in a rat model. Clinically, it should be used in the palliative treatment of patients with leptomeningeal metastases.
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