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

  • Authors:
    • Rajshree R. Mewani
    • Wenhua Tang
    • Aquilur Rahman
    • Anatoly Dritschilo
    • Imran Ahmad
    • Usha N. Kasid
    • Prafulla C. Gokhale
  • View Affiliations

  • Published online on: May 1, 2004     https://doi.org/10.3892/ijo.24.5.1181
  • Pages: 1181-1188
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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.

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May 2004
Volume 24 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Mewani, R.R., Tang, W., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U.N., & Gokhale, P.C. (2004). 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. International Journal of Oncology, 24, 1181-1188. https://doi.org/10.3892/ijo.24.5.1181
MLA
Mewani, R. R., Tang, W., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U. N., Gokhale, P. C."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". International Journal of Oncology 24.5 (2004): 1181-1188.
Chicago
Mewani, R. R., Tang, W., Rahman, A., Dritschilo, A., Ahmad, I., Kasid, U. N., Gokhale, P. C."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". International Journal of Oncology 24, no. 5 (2004): 1181-1188. https://doi.org/10.3892/ijo.24.5.1181