Intratumoral generation of 5-fluorouracil mediated by an antibody-cytosine deaminase conjugate in combination with 5-fluorocytosine.
Cancer Res
; 54(10): 2719-23, 1994 May 15.
Article
em En
| MEDLINE
| ID: mdl-8168103
ABSTRACT
Cytosine deaminase (CD) is a microbial enzyme that can convert the antifungal agent 5-fluorocytosine (5-FC) into the antitumor agent, 5-fluorouracil (5-FU). The enzyme was chemically conjugated to the L6 monoclonal antibody, forming a conjugate that bound to antigens on the H2981 lung adenocarcinoma. Detailed studies were undertaken to determine the extent to which L6-CD generated 5-FU in tumor-bearing mice. Very high tumorblood ratios of L6-CD (421) in vivo were obtained by injecting the conjugate followed 24 h later by an antiidiotypic antibody that could bind to circulating L6-CD but not to L6-CD that was bound to H2981 cells. As a result, significantly more 5-FC could be administered (> 800 mg/kg) than 5-FU (90 mg/kg). L6-CD converted 5-FC into 5-FU such that the L6-CD/antiidiotypic monoclonal antibody/5-FC combination resulted in 17 times more intratumoral 5-FU compared to systemic 5-FU administration. The conversion was antigen dependent since much lower intratumoral 5-FU levels were obtained in H3719 tumors that failed to localize L6-CD. The conversion of 5-FC into 5-FU was low in blood, kidneys, and liver. This demonstrates that a major increase in intratumoral drug concentrations can be attained with an monoclonal antibody-enzyme conjugate in combination with an anticancer prodrug compared to systemic drug therapy.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Flucitosina
/
Fluoruracila
/
Anticorpos Monoclonais
/
Nucleosídeo Desaminases
Limite:
Animals
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
1994
Tipo de documento:
Article