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: Aikaterini Vassilakos, Yoon Lee, Stéphane Viau, Ningping Feng, Hongnan Jin, Viengthong Chai, Ming Wang, Tina Avolio, Jim Wright, Aiping Young
• Journal: International journal of oncology (Int J Oncol) Vol. 34 Issue 1 Pg. 33-42 (Jan 2009) ISSN: 1019-6439 [Print] Greece
• PMID: 19082475 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Interferon-alpha
• Oligodeoxyribonucleotides
• GTI2040
• Ribonucleotide Reductases

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• Drug Therapy, Combination
• Genetic Therapy
• Humans
• Immunoenzyme Techniques
• Interferon-alpha (therapeutic use)
• Kidney Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, SCID
• Oligodeoxyribonucleotides (therapeutic use)
• Ribonucleotide Reductases (antagonists & inhibitors, genetics)
• Transplantation, Heterologous
• Tumor Cells, Cultured