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TNFerade Biologic: preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene.
Rasmussen, Henrik; Rasmussen, Camilla; Lempicki, Maria; Durham, Rebecca; Brough, Douglas; King, C Richter; Weichselbaum, Ralph.
Afiliação
  • Rasmussen H; GenVec Inc., Gaithersburg, Maryland 20878, USA. hrasmussen@genvec.com
Cancer Gene Ther ; 9(11): 951-7, 2002 Nov.
Article em En | MEDLINE | ID: mdl-12386834
ABSTRACT
TNFerade Biologic (TNFerade) is a second-generation (E1-, E3-, and E4-deleted) replication-deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha (TNFalpha), regulated by the radiation-sensitive promoter Early Growth Response (Egr-1). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFalpha with minimal toxicity. Three preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune-competent (Balb/c) mice. A total of 80 mice in the nude mouse toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb/c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4x10(9) to 4x10(10) particle units (pu) (4x10(11) pu in the Balb/c study) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb/c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb/c study, 6/40 mice at the top dose (4x10(11) pu) were sacrificed in moribund condition (5/20 in the TNFerade+radiation group, 1/20 in the TNFerade alone group). Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels (4x10(9) and 4x10(10) pu), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFalpha in the tumor homogenate with no "spillover" to plasma, where TNFalpha levels were below the level of detection. Radiation increased intratumoral levels of TNFalpha by a factor of 12 (from 0.998 to 11.55 ng/g). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFalpha without systemic toxicity.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Regiões Promotoras Genéticas / Fator de Necrose Tumoral alfa Limite: Animals / Humans Idioma: En Ano de publicação: 2002 Tipo de documento: Article
Buscar no Google
Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Regiões Promotoras Genéticas / Fator de Necrose Tumoral alfa Limite: Animals / Humans Idioma: En Ano de publicação: 2002 Tipo de documento: Article