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.
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.
Mewani
Rajshree R
RR
Department of Radiation Medicine, Georgetown University Medical Center, NW, Washington, DC 20057, USA.
Tang
Wenhua
W
Rahman
Aquilur
A
Dritschilo
Anatoly
A
Ahmad
Imran
I
Kasid
Usha N
UN
Gokhale
Prafulla C
PC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D017239:Paclitaxel / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D008081:Liposomes; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel