A novel parasite-derived suicide gene for cancer gene therapy with specificity for lung cancer cells.
The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) expressed by the parasite Trypanosoma brucei (Tb) can convert allopurinol, a purine analogue, to corresponding nucleotides with greater efficiency than its human homologue. We have developed a retroviral system that expresses the parasitic enzyme and tested its capacity to activate the prodrug allopurinol to a cytotoxic metabolite. Cytotoxicity assays demonstrated that five non-small cell lung carcinoma cell lines transduced with the construct were sensitized to the prodrug by 2.1- to 7.6-fold compared with control values. This selectivity was not observed in seven other cell lines also expressing the construct, such as breast carcinoma. Assays indicated that enhanced cytotoxicity to allopurinol correlated with induction of apoptosis in lung cancer cells. The selectivity of this suicide gene was not explained either by the TbHGPRT expression or by the allopurinol accumulation. Our study shows that this novel system may represent a therapeutic tool for gene prodrug targeting of lung cancer, considering the fact that allopurinol is well tolerated in humans.
Trudeau
C
C
Department of Pharmacology, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Yuan
S
S
Galipeau
J
J
Benlimame
N
N
Alaoui-Jamali
M A
MA
Batist
G
G
D000493:Allopurinol / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D005804:Genes, Lethal / Q000235:genetics*; D017125:Genes, Protozoan / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008856:Microscopy, Fluorescence; D009928:Organ Specificity; D011355:Prodrugs / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics
D011355:Prodrugs; D000493:Allopurinol; D007041:Hypoxanthine Phosphoribosyltransferase