title: GTI-2040 displays cooperative anti-tumor activity when combined with interferon alpha against human renal carcinoma xenografts.
abstract: GTI-2040, an antisense oligonucleotide targeting the small subunit of ribonucleotide reductase, acts as an anti-tumor agent in animal models of human cancer. In the present study, the anti-tumor activity of GTI-2040, in combination with interferon alpha (IFNalpha) was investigated against human renal cell carcinoma tumors xenografted into mice. The human renal cell carcinoma cell lines, Caki-1 and A498 were sensitive to IFNalpha both in vitro and when implanted into mice. In combination with GTI-2040 there were cooperative effects at intermediate doses of the two agents and complete tumor regression at higher combination doses. A control oligonucleotide was not effective as a monotherapy and did not improve the efficacy of IFNalpha. The effect of combination treatment on apoptosis and proliferation of tumor cells, isolated from xenografted tumors, was examined by histochemistry. GTI-2040 increased the percentage of cells undergoing apoptosis with a concomitant decrease in proliferation. IFNalpha alone had no effect but in combination with GTI-2040 resulted in increased apoptosis and decreased proliferation compared to GTI-2040 alone. Taken together these results expand the potential clinical applications of GTI-2040 to include combination therapy with IFNalpha.
authors.affiliation: Lorus Therapeutics Inc., Toronto, Ontario M9W 4Z7, Canada.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Vassilakos
authors.forename: Yoon
authors.initials: Y
authors.lastname: Lee
authors.forename: Stéphane
authors.initials: S
authors.lastname: Viau
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.forename: Hongnan
authors.initials: H
authors.lastname: Jin
authors.forename: Viengthong
authors.initials: V
authors.lastname: Chai
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Tina
authors.initials: T
authors.lastname: Avolio
authors.forename: Jim
authors.initials: J
authors.lastname: Wright
authors.forename: Aiping
authors.initials: A
authors.lastname: Young
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D016898:Interferon-alpha / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C464617:GTI2040; D012264:Ribonucleotide Reductases