Liposomal formulation of 5-fluorocytosine in suicide gene therapy with cytosine deaminase--for colorectal cancer.
It is generally accepted that successful gene therapy depends on two major factors: tumor-specific expression of a therapeutic gene and the efficient transfer of a therapeutic gene to tumor cells. For gene-directed enzyme prodrug therapy (GDEPT) involving Escherichia coli cytosine deaminase (CD) and 5-fluorocytosine (5-FC), several tumor-specific promoters and virus-based vectors were used. No attention whatsoever was paid to the way of 5-FC delivery to solid tumors, despite the fact that the delivery of drugs to such tumors is generally low because of their insufficient transfer from the blood. To compare the effectiveness of GDEPT with free and liposomal 5-FC, the prodrug was encapsulated in liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (1:1). When the liposomal form of 5-FC was administered i.v., mice treated with a dose of 5mg of liposomal 5-FC/kg body weight for 10 days, showed complete regression of transplanted tumors and complete cure was observed, whereas in animals treated with the same amounts of the free prodrug, 50% tumor regression and only insignificantly prolonged median survival were found. In summary, these results showed a remarkable enhancement of the antitumor effects of the liposomal form of 5-FC in comparison with the free prodrug. Therapy with liposomal 5-FC thus represents a new approach to achieving a high local concentration of the prodrug for suicide gene therapy using E. coli CD.
Chaszczewska-Markowska
Monika
M
Departments of Immunochemistry and Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigela. 12, 53-114 Wrocław, Poland.
Stebelska
Katarzyna
K
Sikorski
Aleksander
A
Madej
Janusz
J
Opolski
Adam
A
Ugorski
Maciej
M
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000401:mortality / Q000628:therapy*; D043525:Cytosine Deaminase / Q000627:therapeutic use*; D005437:Flucytosine / Q000008:administration & dosage* / Q000633:toxicity; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection
D008081:Liposomes; D005437:Flucytosine; D043525:Cytosine Deaminase