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).
Doi
Yusuke
Y
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Science, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan.
Okada
Tomoko
T
Matsumoto
Haruna
H
Ichihara
Masako
M
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010094:Oxonic Acid / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000737:chemistry; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects*
D004338:Drug Combinations; D008081:Liposomes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C079198:S 1 (combination); D005641:Tegafur; D011092:Polyethylene Glycols; D010094:Oxonic Acid