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, x 10/16) and cisplatin (i.v., 11.0 mg/kg/dose, x 3), epirubicin (EPI) (i.v., 9.0 mg/kg/dose, x 3) or mitoxantrone (MTO) (W., 2.5 mg/kg/dose, x 3) 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, x 10/13) with docetaxel (Taxotere) (i.v., 5, 7.5 or 10 mg/kg/dose, x 2/4) 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, x 10/13) with gemcitabine (i.v., 75 mg/kg/dose, x 4/6) 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, x 10) 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, x 1 or 7.5 mg/kg/dose, x 2; 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 (C) 2004 Lippincott Williams Wilkins.