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MS-209, a Quinoline-Type Reversal Agent, Potentiates Antitumor Efficacy of Docetaxel in Multidrug-Resistant Solid Tumor Xenograft Models1

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MS-209, a Quinoline-Type Reversal Agent, Potentiates Antitumor Efficacy of Docetaxel in Multidrug-Resistant Solid Tumor Xenograft Models1 582 Vol. 8, 582–588, February 2002 Clinical Cancer Research MS-209, a Quinoline-type Reversal Agent, Potentiates Antitumor Efficacy of Docetaxel in Multidrug-resistant Solid Tumor Xenograft Models1 Mikihiko Naito, Yasuhiro Matsuba, Shigeo Sato, indicate that MS-209 could be a clinically useful drug to Hiroshi Hirata, and Takashi Tsuruo2 modulate MDR in docetaxel therapy. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032 [M. N., Y. M., T. T.]; Cancer INTRODUCTION Chemotherapy Center, Japanese Foundation for Cancer Research, Chemotherapy is indispensable for cancer treatment, as is Toshima-ku, Tokyo 170-0012 [S. S., T. T.]; Drug Discovery Institute, surgical excision and radiation therapy. However, the emer- Nihon Schering K. K. 1900-1, Togo, Mobara-shi, Chiba, 297-0017 gence of cancer cells resistant to chemotherapy often hampers [Y. M.]; and Preclinical Development Department, Nihon Schering 3 K. K. 6-64, Nishimiyahara 2-chome, Yodogawa-ku, Osaka, 532-0004 treatment results. A major mechanism is MDR, which is caused [H. H.] Japan by overexpression of a drug-efflux pump, such as P-gp, on the surface of cancer cells (1–3). In MDR cancer cells, the intra- cellular concentration of drugs is reduced because of the drug ABSTRACT efflux pump. The existence of multidrug-resistant (MDR) cells in To overcome MDR, enormous efforts have been made to cancer is a major obstacle to effective cancer chemotherapy. find an inhibitor of the drug-efflux pump, and various com- Expression of P-glycoprotein (P-gp) in cancer cells causes pounds, such as verapamil, cyclosporin, quinidine, tamoxifen, resistance against paclitaxel and docetaxel, as well as against progesterone, reserpine, and others have been reported to over- vincristine and doxorubicin (ADM). MS-209 is a novel come MDR in vitro (4–9). However, most of these compounds MDR-reversal agent currently under clinical evaluation, have had disappointing results in animal studies because of their which is shown to be active against ADM and vincristine dose-limiting toxicity. Hence, a new reversal agent with a potent resistance in MDR cancer cells in vitro and in vivo. In this in vivo effect has been expected to develop. paper, we report the combined effect of MS-209 with do- We reported previously a series of quinoline derivatives cetaxel in various MDR cancer cell lines that express P-gp. that shows MDR-reversing activity in K562/ADM, a human MS-209 at 3 ␮M effectively overcame docetaxel resistance in leukemia cell line that overexpresses P-gp (10). Among them, MDR cancer cells, and this concentration was achieved in MS-209 (Fig. 1) was one of the most potent quinoline deriva- blood plasma for > 7 h without serious toxicity. To study the tives that can reverse MDR in vitro at a clinically achievable effect of MS-209 in a clinically relevant model, we compared concentration (3 ␮M; when 600 mg of MS-209 was p.o. admin- the antitumor efficacy of docetaxel alone with that of do- istered to human, maximum plasma concentration, time to reach cetaxel combined with MS-209 at equitoxic doses in estab- maximum plasma concentration, and half life were 21.0 Ϯ 4.4 lished solid tumor xenograft models. Treatment with do- ␮M, 0.75 Ϯ 0.22 h, and 2.25 Ϯ 0.47 h, respectively; n ϭ 6). In cetaxel alone at the maximal tolerated dose (MTD) showed addition, oral administration of MS-209 enhanced antitumor an apparent antitumor activity to an intrinsically resistant activity of ADM and vincristine in vivo (11, 12) and, given HCT-15 tumor xenograft, and MS-209 additionally potenti- alone, did not show serious toxicity at doses up to 2000 mg/kg. ated the antitumor activity of docetaxel. Against a MCF-7/ Thus, MS-209 is a promising MDR reversal drug, and the ADM tumor xenograft expressing larger amounts of P-gp, compound is now under clinical evaluation in Japan (Phase III) docetaxel alone at the MTD showed no antitumor activity, and Europe (Phase I). whereas the MTD of docetaxel combined with MS-209 Docetaxel is a newly developed anticancer drug that stabi- greatly reduced MCF-7/ADM tumor growth. These results lizes the microtubule and is clinically useful to treat breast and lung cancers. It was demonstrated to be a substrate of human P-gp (13), and one of the important mechanisms of docetaxel resistance is an overexpression of P-gp in cancer cells (14, 15). In this paper, we report the reversal activity of MS-209 to Received 9/6/00; revised 7/24/01; accepted 11/1/01. docetaxel resistance in various MDR cancer cells expressing The costs of publication of this article were defrayed in part by the P-gp. Moreover, we demonstrated the usefulness of MS-209 in payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by a special grant for advanced research on cancer and grants-in-aid for cancer research from the Ministry of Education, 3 The abbreviations used are: MDR, multidrug-resistant; P-gp, P-glyco- Culture, Sports, Science and Technology, Japan. protein; MTD, maximal tolerated dose; ADM, doxorubicin; MRP, 2 To whom requests for reprints should be addressed, at Institute of multidrug resistance-associated protein; AUC, area under plasma con- Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo- centration curve; RT-PCR, reverse transcription-PCR; HPLC, high- ku, Tokyo 113-0032, Japan. Phone: 81-3-5841-7861; Fax: 81-3-5841- performance liquid chromatography; TV, tumor volume; RTV, relative 8487; E-mail: [email protected]. tumor volume. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2002 American Association for Cancer Research. Clinical Cancer Research 583 experiments, tumor lump was passaged at the axillary region of BALB/c-nu/nu mice. Growth Inhibition Assays. Cancer cells were seeded in 96-well plates at a density of 1500–3000 cells/well in 100 ␮lof culture medium. After a 24-h culture, 50 ␮l of MS-209 solution and 50 ␮l of docetaxel solution were sequentially added and incubated for an additional 72 h. Cell growth was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (16). Growth rate was expressed as the ratio of absorbance Fig. 1 Chemical structure of MS-209 of the drug-treated wells to that of control wells, and concen- trations of docetaxel that provided IC50 were determined. Semiquantitative RT-PCR. Total cellular RNA was ex- tracted from the above 13 cell lines with a RNeasy Mini kit (Qiagen). RT-PCR for MDR1 was conducted using the forward docetaxel therapy against MDR cancers by comparing the anti- primer 5Ј- AAGCGAAGCAGTGGTTCAGG-3Ј and the reverse tumor effect at equitoxic doses of docetaxel alone with the primer 5Ј-ACCAACTCACATCCTGTCTG-3Ј with One Step combination of docetaxel and MS-209 in established solid tu- RNA PCR kit (TaKaRa Shuzo, Tokyo, Japan). The primers mor xenograft models. for ␤-actin were 5Ј-GATGAGGCCCAGAGCAAGAG-3Ј (for- ward) and 5Ј-AGGCGTACAGGGACAGCACA-3Ј (reverse). MATERIALS AND METHODS The thermal cycles were as follows: (a) 1 cycle of 50°C, 30 min; Chemical Agents. MS-209 was synthesized by Mitsui 95°C, 5 min; (b) 21 cycles of 95°C, 20 s; 60°C, 1 min; and (c) Chemicals Inc. (Tokyo, Japan) and kindly provided by Mitsui hold at 4°C. The PCR products were then run at 100 V on a 2% Pharmaceuticals Inc. (Tokyo, Japan). Docetaxel was kindly agarose gel and visualized by ethidium bromide staining. The provided by Rhoˆne-Poulenc Rorer Japan Inc. (Tokyo, Japan). MDR1 bands were quantified with Scion Image software (Scion For in vitro studies, MS-209 was dissolved in DMSO Corp.) and normalized with that of ␤-actin control. before diluting with culture medium (final concentration of Western Blot Analysis. Cells were washed twice with DMSO was 0.1–0.01%). Docetaxel was first dissolved in eth- ice-cold PBS(Ϫ), dissolved in PBS(Ϫ) containing 0.5% Triton anol at 20 mg/ml (stored at 20°C), then diluted more than 25 ϫ (v/v), and centrifuged at 15,000 rpm (radius 6 cm) for 5 min at with sterilized, distilled water. It was additionally diluted with 4°C to remove insoluble fraction. The supernatant was used as culture medium to the desired concentration (final concentration cell lysate. Aliquots of cell lysate (30 ␮g of protein) were of ethanol was Ͻ0.01%). electrophoresed on an SDS-polyacrylamide gradient gel (4– For in vivo experiments, MS-209 was suspended in sterilized, 20%) and then electrophoretically transferred to a nitrocellulose distilled water containing 0.1% Tween 80. Docetaxel was first membrane. The nitrocellulose membrane was probed with an dissolved in ethanol, then an equal volume of polysorbate 80 was anti-P-gp monoclonal antibody, C-219 (Centocor, Inc.), at a added, and the final dilution was obtained with 5% glucose in water dilution of 1:50 (v/v), and horseradish peroxidase-conjugated (ethanol/polysorbate 80/5% glucose ϭ 5/5/90; v/v/v). antimouse immunoglobulin (Amersham) was used as the second Animals and Tumor Cell Lines. Female BALB/c-nu/nu antibody. Expression of human P-gp was visualized using an mice were purchased from Charles River Japan, Inc. (Yoko- enhanced chemiluminescence Western Blotting kit (Amer- hama, Japan). They were maintained under specific pathogen- sham). The intensity of each band was quantified using Scion free conditions. Seven-week-old mice were used for this study. Image software (Scion Corp.). Human epidermal carcinoma KB-3-1 and its colchicine- Cell Cycle Analysis. K562, K562/VCR, and K562/ADM resistant subline KBCh8-5-11 were provided by Dr.
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