Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: Reversing tumor radioresistance and effecting cure

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 4; pp. 1396 - 1402
• Main Authors: COWEN, Rachel L, WILLIAMS, Kaye J, CHINJE, Edwin C, JAFFAR, Mohammed, SHEPPARD, Freda C. D, TELFER, Brian A, WIND, Natasha S, STRATFORD, Ian J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-02-2004
• Subjects: Adenoviridae - genetics; Adenovirus; Animals; Antineoplastic agents; Biological and medical sciences; Cell Hypoxia; Female; Genetic Therapy; Humans; L-Lactate Dehydrogenase - genetics; Medical sciences; Mice; NADPH-Ferrihemoprotein Reductase - genetics; Neoplasms, Experimental - therapy; Pharmacology. Drug treatments; Radiation Tolerance; Radiotherapy, Adjuvant; Response Elements; Tirapazamine; Triazines - therapeutic use; Tumors; Target; Oxygen; Targeting; Cure; Adjuvant treatment; Triazine derivatives; Environmental factor; Hypoxia; Malignant tumor; Gene therapy; Tirapazamine
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-2698

Solid tumors are characterized by regions of hypoxia that are inherently resistant to both radiotherapy and some chemotherapy. To target this resistant population, bioreductive drugs that are preferentially toxic to tumor cells in a hypoxic environment are being evaluated in clinical trials; the lead compound, tirapazamine (TPZ), is being used in combination with cisplatin and/or with radiotherapy. Crucially, tumor response to TPZ is also dependent on the cellular complement of reductases. In particular, NADPH:cytochrome P450 reductase (P450R) plays a major role in the metabolic activation of TPZ. In a gene-directed enzyme prodrug therapy (GDEPT) approach using adenoviral delivery, we have overexpressed human P450R specifically within hypoxic cells in tumors, with the aim of harnessing hypoxia as a trigger for both enzyme expression and drug metabolism. The adenovirus used incorporates the hypoxia-responsive element (HRE) from the lactate dehydrogenase gene in a minimal SV40 promoter context upstream of the cDNA for P450R. In a human tumor model in which TPZ alone does not potentiate radiotherapeutic outcome (HT1080 fibrosarcoma), we witnessed complete tumor regression when tumors were virally transduced before treatment.