Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models.

Abstract

Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.

• Authors: Rajshree R Mewani, Wenhua Tang, Aquilur Rahman, Anatoly Dritschilo, Imran Ahmad, Usha N Kasid, Prafulla C Gokhale
• Journal: International journal of oncology (Int J Oncol) Vol. 24 Issue 5 Pg. 1181-8 (May 2004) ISSN: 1019-6439 [Print] Greece
• PMID: 15067340 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liposomes
• Oligonucleotides, Antisense
• Doxorubicin
• Proto-Oncogene Proteins c-raf
• Paclitaxel

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy, genetics)
• Doxorubicin (administration & dosage)
• Female
• Humans
• Liposomes
• Lung Neoplasms (drug therapy, genetics)
• Male
• Mice
• Mice, Nude
• Oligonucleotides, Antisense (administration & dosage)
• Paclitaxel (administration & dosage)
• Prostatic Neoplasms (drug therapy, genetics)
• Proto-Oncogene Proteins c-raf (genetics, metabolism)
• Tumor Cells, Cultured (transplantation)
• Xenograft Model Antitumor Assays (methods)