Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine.

Abstract

Raf-1 protein serine/threonine kinase plays an important role in cell proliferation and cell survival. We have previously described a novel cationic liposome-entrapped formulation of raf antisense oligodeoxyribonucleotide (LErafAON) and its use as a radiosensitizer. The aim of this study was to examine the effect of combination of LErafAON and a chemotherapeutic agent on growth of human prostate (PC-3) and pancreatic tumor xenografts in athymic mice (Aspc-1 and Colo 357). In PC-3 tumor-bearing mice, administration of a combination of LErafAON (i.v., 25 mg/kg/dose, x10/16) and cisplatin (i.v., 11.0 mg/kg/dose, x3), epirubicin (EPI) (i.v., 9.0 mg/kg/dose, x3) or mitoxantrone (MTO) (i.v., 2.5 mg/kg/dose, x3) led to enhanced tumor growth inhibition as compared with single agents (LErafAON+cisplatin versus cisplatin, p<0.0002, n=8; LErafAON+EPI versus EPI, p<0.0001, n=6; LErafAON+MTO versus MTO, p<0.05, n=5). In prostate or pancreatic tumor-bearing mice, combination of LErafAON (i.v., 25 mg/kg/dose, x10/13) with docetaxel (Taxotere) (i.v., 5, 7.5 or 10 mg/kg/dose, x2/4) led to tumor regression or enhanced growth inhibition as compared with single agents (PC-3: LErafAON+Taxotere versus Taxotere, p<0.02, n=7; Aspc-1: LErafAON+Taxotere versus Taxotere, p<0.03, n=5; Colo 357: LErafAON+Taxotere versus Taxotere, p<0.04, n=7). Combination of LErafAON (i.v., 25 mg/kg/dose, x10/13) with gemcitabine (i.v., 75 mg/kg/dose, x4/6) also caused a significant tumor growth inhibition in the two pancreatic carcinoma models studied (Aspc-1: LErafAON+gemcitabine versus gemcitabine, p<0.0001, n=7; Colo 357: LErafAON+gemcitabine versus gemcitabine, p<0.002, n =5). LErafAON treatment (i.v., 25 mg/kg/dose, x10) caused inhibition of Raf-1 protein expression in these tumor tissues (around 25-60%, n=4-7). Interestingly, Taxotere treatment per se also led to decreased steady state level of Raf-1 protein in PC-3 and Aspc-1 tumor tissues (i.v., 10 mg/kg/dose, x1 or 7.5 mg/kg/dose, x2; around 25-80%, n=2/6). Present studies demonstrate enhanced tumor growth inhibition or regression in response to a combination of a chemotherapeutic drug and LErafAON. These data provide a proof-of-principle for the clinical use of LErafAON in combination with chemotherapy for cancer treatment.

• Authors: Jin Pei, Chuanbo Zhang, Prafulla C Gokhale, Aquilur Rahman, Anatoly Dritschilo, Imran Ahmad, Usha N Kasid
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 3 Pg. 243-53 (Mar 2004) ISSN: 0959-4973 [Print] England
• PMID: 15014358 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Liposomes
• Oligonucleotides, Antisense
• Taxoids
• Deoxycytidine
• Docetaxel
• Epirubicin
• Mitoxantrone
• Proto-Oncogene Proteins c-raf
• Cisplatin
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Docetaxel
• Epirubicin (administration & dosage)
• Female
• Humans
• Liposomes
• Male
• Mice
• Mice, Nude
• Mitoxantrone
• Oligonucleotides, Antisense (administration & dosage)
• Proto-Oncogene Proteins c-raf (administration & dosage, biosynthesis)
• Taxoids (administration & dosage)
• Xenograft Model Antitumor Assays (methods)
• Gemcitabine