Potentiation of the antitumor activity by a novel quinoline compound, MS-209, in multidrug-resistant solid tumor cell lines.
A novel quinoline compound, MS-209, was examined for its ability to reverse multidrug resistance (MDR) in several murine and human MDR solid tumor cell lines both in vitro and in vivo. MS-209 strongly reversed drug resistance to adriamycin (ADM) and vincristine (VCR) in acquired MDR tumor cell lines, 2780AD and KB-C1. In addition, MS-209 enhanced the cytotoxic effect of ADM and VCR on various human and murine cell lines. Particularly in 4-1St cells, which are extremely resistant to ADM and VCR, MS-209 at a concentration of 3 microM enhanced the cytotoxicity of ADM and VCR, 88- and 350-fold, respectively. MS-209 administered orally, together with ADM, enhanced the antitumor activity of ADM on Colon 26 and 4-1St tumors implanted subcutaneously (SC) in mice; the antitumor effect of ADM plus MS-209 was higher than that of ADM alone at the maximum tolerated dose (MTD). Furthermore, the coadministration schedules of MS-209 to attain the highest potentiation of ADM activity were examined using Colon 26 tumors. The maximum antitumor activity was obtained when MS-209 was administered on the same day as ADM. MS-209 administered a day before the ADM injection exhibited no potentiation effect, whereas MS-209 administered a day after the ADM injection showed a moderate effect. The effect of MS-209 was weaker when administered in a fractionated manner than when administered as a single dose. The results presented in this article suggest that MS-209 is an effective agent to overcome MDR in cancer chemotherapy.
Nakanishi
O
O
Institute of Biological Science, Mitsui Pharmaceuticals, Inc., Chiba, Japan.
Baba
M
M
Saito
A
A
Yamashita
T
T
Sato
W
W
Abe
H
H
Fukazawa
N
N
Suzuki
T
T
Sato
S
S
Naito
M
M
Tsuruo
T
T
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D011804:Quinolines / Q000627:therapeutic use* / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D011804:Quinolines; C087719:dofequidar; D014750:Vincristine; D004317:Doxorubicin