Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine.
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.
Pei
Jin
J
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Zhang
Chuanbo
C
Gokhale
Prafulla C
PC
Rahman
Aquilur
A
Dritschilo
Anatoly
A
Ahmad
Imran
I
Kasid
Usha N
UN
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D019908:Proto-Oncogene Proteins c-raf / Q000008:administration & dosage* / Q000096:biosynthesis; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000093542:Gemcitabine
D008081:Liposomes; D016376:Oligonucleotides, Antisense; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D015251:Epirubicin; D008942:Mitoxantrone; D019908:Proto-Oncogene Proteins c-raf; D002945:Cisplatin; D000093542:Gemcitabine