Intratumoral administration of methotrexate bound to activated carbon particles: antitumor effectiveness against human colon carcinoma xenografts and acute toxicity in mice.
We previously developed a new formulation of methotrexate (MTX) that is adsorbed onto a suspension of activated carbon particles (MTX-CH) and reported the usefulness of local administration in murine tumors. The present study examines the effects of human colon carcinoma (LoVo) xenografts and the acute toxicity of MTX-CH compared with MTX aqueous solution (MTX-AQ) in mice. In therapeutic experiments, LoVo cells were implanted into the backs of BALB/c nude mice. When the cells had developed into tumors, we performed an intratumoral administration of a weekly dose of 30 mg/kg. The MTX concentration in the tumor was compared between the MTX-CH group and MTX-AQ group. In experiments on acute toxicity, MTX-CH and MTX-AQ were injected subcutaneously in BDF1 mice, and intoxication symptoms, changes in body weight, and date of death were recorded. In the therapeutic experiments, intratumoral administration of MTX-CH was much more effective in suppressing the tumor growth compared with MTX-AQ. In experiments of acute toxicity, the death time of the MTX-CH group was delayed to a greater extent, and the 50% lethal dose (LD(50)) values of MTX-CH were lower than those of MTX-AQ. The LD(50) values of MTX-CH are 75 times higher than the efficacious dose of 30 mg/kg. The present results suggest that intratumoral administration of MTX-CH is useful for local therapy and the therapeutic dose of MTX-CH can be safely injected subcutaneously.
Nakase
Yuen
Y
Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji Kajiicho 465, Kamigyo-ku, Kyoto 602-8566, Japan. yuen-n@koto.kpu-m.ac.jp
Hagiwara
Akeo
A
Kin
Syuichi
S
Fukuda
Ken-ichirou
K
Ito
Tadao
T
Takagi
Tsuyoshi
T
Fujiyama
Jyunshin
J
Sakakura
Chohei
C
Otsuji
Eigo
E
Yamagishi
Hisakazu
H
D000818:Animals; D001344:Autopsy; D001835:Body Weight / Q000187:drug effects; D002606:Charcoal / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D023041:Xenograft Model Antitumor Assays
D002606:Charcoal; D008727:Methotrexate