The use of cationic liposomes DC-CHOL/DOPE and DDAB/DOPE for direct transfer of Escherichia coli cytosine deaminase gene into growing melanoma tumors

Gene Ther. 1996 Nov;3(11):1026-31.

Abstract

An attempt was made to use simple cationic liposomes DC-Chol/DOPE and DDAB/DOPE (DC-Chol is 3 beta (N(N',N-dimethylaminoethane) carbamoyl) cholesterol, DDAB is dimethyldioctadecyl ammonium bromide and DOPE is dioleoylphosphatidylethanolamine) for transfer of Escherichia coli cytosine deaminase 'suicide' gene under the control of tissue-specific tyrosinase gene promoter directly into the murine melanoma B16(F10) tumor. Several repeated intratumoral injections of DNA-liposome complexes followed by intraperitoneal administrations of 5-fluorocytosine, which is converted to 5-fluorouracil, caused strong retardation of murine melanoma B16(F10) tumor growth and, in some cases, rejection of the pre-established tumor. The inhibition of tumor growth expressed as the increased survival of mice is better seen in the case of using DNA-DDAB/DOPE complexes as compared to DNA-DC-Chol/DOPE ones. It seems that the observed therapeutic effect appears to result from several factors: 5-fluorouracil generation by transfected cells, liposome toxicity (DDAB is more toxic than DC-Chol and hence more tumor cells are killed), increased transfection efficiency of surviving cancer cells (in this case DDAB is a better transfection agent than DC-Chol) and, finally, the bystander effect which causes destruction of cells untransfected with CD gene by easily diffusible 5-fluorouracil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Cations
  • Cholesterol / analogs & derivatives*
  • Cholesterol / chemistry
  • Cytosine Deaminase
  • Drug Carriers
  • Escherichia coli / enzymology*
  • Fluorouracil / pharmacology*
  • Gene Transfer Techniques*
  • Liposomes
  • Melanoma / therapy*
  • Mice
  • Neoplasms, Experimental / therapy
  • Nucleoside Deaminases / genetics*
  • Phosphatidylethanolamines / chemistry*
  • Quaternary Ammonium Compounds / chemistry*

Substances

  • Antimetabolites, Antineoplastic
  • Cations
  • Drug Carriers
  • Liposomes
  • Phosphatidylethanolamines
  • Quaternary Ammonium Compounds
  • didodecyldimethylammonium
  • 3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol
  • 1,2-dielaidoylphosphatidylethanolamine
  • Cholesterol
  • Nucleoside Deaminases
  • Cytosine Deaminase
  • Fluorouracil