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Cancer Gene Therapy by Thyroid Hormone-mediated Expression of Toxin Genes¹

Departamento de Bioquímica y Biología Molecular, Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco 28049 Madrid, Spain [V. M., M. L. C., P. d. F., M. I.]; Institute Medicina Sperimentale, Consiglio Nazionale delle Ricerche and Laboratorio di Oncogenesi Molecolare, Institute Regina Elena, 00161 Rome, Italy [A. F.]; and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nac. Rosario, 2000-Rosario, Argentina [N. B. C.]

Many of the strategies developed in the last few years to treat cancer by gene therapy are based on putative killer-suicide genes whose products convert a prodrug into a toxic compound. When the therapy is applied to humans, a vector carrying the killer gene is first inoculated into the tumor of the patient, who 1 week later receives the corresponding prodrug that will selectively kill the cells able to process it to its toxic derivative. A strategy that obviates the need for a prodrug to destroy the cancer cells would be preferable because the patient would only need one treatment instead of two consecutive ones. In the following study, we describe the construction of retroviral vectors in which a reporter or a toxin gene (either the Pseudomonas exotoxin or the Ricinus communis toxin, ricin) is placed under the control of the thyroid hormone (T₃) regulatable promoter of the rat myelin basic protein (MBPp). We demonstrate that the expression of these genes under the control of MBPp is regulated by T₃ in vitro and in vivo. In vitro, the MBPp is switched off when T₃ is removed from the serum of the culture medium, allowing the production of retroviruses carrying the toxic gene. In vivo, the toxin gene bearing retroviruses is capable of eradicating experimentally induced brain tumors in Wistar rats. The gene therapy strategy described here does not require the use of a prodrug to destroy the neoplastic cells.

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