Combination therapy of metronomic S‐1 dosing with oxaliplatin‐containing polyethylene glycol‐coated liposome improves antitumor activity in a murine colorectal tumor model

Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)‐coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so‐called “enhanced permeability and retention (EPR) effect”. To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S‐1 dosing in combination with oxaliplatin (l‐OHP)‐containing PEG‐coated liposomes was evaluated in a murine colon carcinoma‐bearing mice model. S‐1 is an oral fluoropyrimidine formulation and metronomic S‐1 dosing is a promising alternative to infused 5‐FU in colorectal cancer therapy. Therefore, the combination of S‐1 with l‐OHP may be an alternative to FOLFOX (infusional 5‐FU/leucovorin (LV) in combination with l‐OHP), which is a first‐line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S‐1 dosing with intravenous administration of liposomal l‐OHP formulation exerted excellent antitumor activity without severe overlapping side‐effects, compared with either metronomic S‐1 dosing, free l‐OHP or liposomal l‐OHP formulation alone or metronomic S‐1 dosing plus free l‐OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l‐OHP in the tumor on account of the PEG‐coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S‐1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL). ( Cancer Sci 2010; 101: 2470–2475)