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Postsurgical Oral Administration of Uracil and Tegafur Inhibits Progression of Micrometastasis of Human Breast Cancer Cells in Nude Mice1

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Postsurgical Oral Administration of Uracil and Tegafur Inhibits Progression of Micrometastasis of Human Breast Cancer Cells in Nude Mice1 Vol. 3, 653-659, May 1997 Clinical Cancer Research 653 Postsurgical Oral Administration of Uracil and Tegafur Inhibits Progression of Micrometastasis of Human Breast Cancer Cells in Nude Mice1 Junichi Kurebayashi,2 Mamoru NUkatSUka, inhibited by the administration of either dose of UFT. In Akio Fujioka, Hitoshi Saito, Setsuo Takeda, conclusion, this new pOStSUrgIcal metastasis model may be useful for evaluating the efficacy of agents used in the post- Norio Unemi, Hiroyuki Fukumori, operative adjuvant setting. UFI may be an effective drug for MasafUmi Kurosumi, Hiroshi Sonoo, Inhibiting the progression of mlcrometastasis after surgery. and Robert B. Dickson Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-01, Japan [J. K., INTRODUCTION H. So.]; Taiho Pharmaceutical Co. Ltd., Tokyo 101, Japan EM. N., The efficacy of postoperative adjuvant chemotherapy A. F., H. Sa., S. T., N. U., H. F.]; Department of Pathology, Saitama and/or endocrine therapy in reducing the mortality of breast Cancer Center, Saitama 362, Japan [M. K.]; and Lombardi Cancer cancer patients has been widely accepted on the basis of the data Center, Georgetown University Medical Center, Washington, DC 20007 [R. B. D.] from many prospective clinical trials (1-3). These agentsused in the postoperative adjuvant setting have already been proven to be effective in the treatment of advanced breast cancer. The ABSTRACT antitumor activity of these agents is believed to be involved in We recently established a metastasis model In nude inhibition of the progression of micrometastasis, which may mice using the MKL-4 cell line, a contransfectant of the already exist at the time of surgery. However, evaluation of such MCF-7 human breast cancer cell line withfgf-4 and lacZ in an inhibitory effect in animal experimental models is hard which micrometastases in several organs can be quantita- because of the difficulty in quantitatively measuring the degree lively observed. First, to develop a new postsurgical metas- of micrometastasis in animal organs. Sledge et a! (4) recently tasis model, we investigated the timing of occurrence of introduced a new postoperative metastasis model in nude mice micrometastasis and the influence of tumor removal on the using a human breast cancer cell line, MDA-MB-435 (5). They progression of micrometastasis in this model. Micrometas- reported that a matrix metalloproteinase inhibitor, Batimastat, tases into lymph nodes and lungs were detected 3 weeks inhibited the regrowth of primary tumors and reduced the num- after the cell injections. Tumor removal 3 weeks after the ber and volume of macroscopic lung metastases after the pri- injections significantly enhanced the progression of micro- mary tumor removal. However, neither any promoting effect of metastasis into lymph nodes and bone. Second, to study the the primary tumor removal nor any inhibitory effect of the effect of a mixed compound, UVl (a molar ratio of uradil: metalloproteinase inhibitor on the progression of micrometasta- tegafur of 4:1), which has been widely used in the postsur- sis has yet been described. gical adjuvant setting in Japan, 15 or 20 mg/kg UFF were We recently established a new metastasis model in nude administered p.o. for 4 weeks to tumor-bearing mice or to mice using the MKL-4 cell line, a cotransfectant of the MCF-7 mice in which transplanted tumors were resected 3 weeks human breast carcinoma cell line with a potent angiogenic factor after the injections. Either dose of UFI significantly inhib- gene, fgf-4, and a genetic marker gene, bacterial lacZ encoding ited the tumor growth as well as the progression of micro- 3-gal.3 Transplantation of MKL-4 cells into the mammary fat metastasis into lymph nodes, lungs, liver, and brain. In pad of female nude mice produces rapid-growing tumors with- addition, enhanced progression of micrometastasis in all out supplementation of estradiol. In addition, whole-organ stain- explored organs by the tumor removal was significantly ing of excised organs from these nude mice for n-gal activity makes metastatic tumor cells blue, helping us to measure the degree of micrometastasis quantitatively. This staining revealed that MKL-4 cells spontaneously metastasized into the lymph nodes, lungs, liver, brain, and bone (bone metastasis was ob- Received 7/22/96; revised 12/I 1/96; accepted 2/4/97. served for the first time in this study). This metastasis model The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked should be useful for evaluating the inhibitory effect of certain advertisement in accordance with 18 U.S.C. Section 1734 solely to agents on metastatic activity (6, 7). Our previous experiment indicate this fact. using this model revealed that a potent antiangiogenic agent, I This work was supported by a grant from the Ministry of Education, TNP-470, clearly inhibits angiogenic activity, tumor growth, Science, Sports and Culture of Japan, by Research Project Grant 7-301 from Kawasaki Medical School (J. K., H. So.), and by NIH Grant 1P50CA58185 (R. B. D.). This article was presented in part at the 32nd Annual Meeting of the American Association of Clinical Oncology, Philadelphia, PA. 2 To whom requests for reprints should be addressed. Phone: 8 1-86- 3 The abbreviations used are: a-gal, -galactosidase; 5-Ri, 5-fluorou- 462-1111; Fax: 81-86-462-1199. racil; PD-ECGF, platelet-derived endotheial growth factor. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 1997 American Association for Cancer Research. 654 Inhibition of Progession of Micrometastasis by liFT and spontaneous metastasis into the lymph nodes and distant degree of micrometastasis using a dissecting microscope. The organs (8). weights of the excised primary tumors were measured. 5-Ri is a widely used antimetabolite for the treatment of Experiment 2. Twenty nude mice were given injections various cancers. Tegafur is a prodrug of 5-Hi which is mainly of MKL-4 cells. Because the results of experiment 1 suggested converted to 5-Hi by microsomal P450 enzymes in the liver (9). that micrometastases may occur 3 weeks after the cell injections, Fujii and colleagues (10-12) found that the coadministration of transplanted MKL-4 tumors were resected in an aseptic condi- uracil and tegafur at a molar ratio of uracil:tegafur of 4:1 tion under ether anesthesia 3 weeks after the injections in the enhanced the concentration of 5-FU in the tumor and produced tumor removal group (10 mice). In the control group (10 mice), maximal antitumor activity in animal model systems. This no surgical maneuver was carried out. All of the mice were mixed compound, UFT (Taiho Pharmaceutical Co. Ltd., Tokyo, sacrificed 7 weeks after the injections. The right axillary lymph Japan), has been widely used in the treatment of breast, gastro- node, distal lymph nodes (contralateral axillary or bilateral intestinal, and head and neck cancers in Japan (13, 14). Because inguinal lymph nodes), lungs, liver, brain, and lumbar vertebral liFT is administered p.o., well tolerated, and devoid of severe bone were excised, stained for 3-gal activity, and observed. The neutropenia, it may provide a better quality of life and cost weights of the excised primary tumors were measured. benefit for patients with advanced cancer. Clinical and experi- Experiment 3. Thirty nude mice were given injections of mental studies of UFT in the treatment ofcolorectal, gastric, and MKL-4 cells. In the treatment groups (10 mice in each group), breast cancers are underway in Western countries (15-22). Very 15 or 20 mg/kg UFF were given p.o. to the mice six times a recently, a pharmacokinetic study showed that p.o. UFT gener- week from 3 to 7 weeks after the injections. The given volume ates a higher peak level of 5-Ri than can be achieved with of the Ufl’ solution was 10 mI/kg for either dose. In the control protracted i.v. 5-Ri infusion (23). Although liFT has also been group (10 mice), the same volume of the vehicle was given in used in the postoperative adjuvant setting for several cancers in the same manner. All of the mice were sacrificed 7 weeks after Japan (24-27), the scientific basis for postoperative UFf ad- the injections. Weights of the excised primary tumors and mice ministration in reducing recurrence and the mortality of cancer were measured. The lymph nodes and distant organs were patients is still unclear. Therefore, we decided to establish a new excised, stained for 3-gal activity, and observed. postoperative metastasis model and to clarify the usefulness of Experiment 4. Thirty nude mice were given injections of postoperative l1FT administration in this model. MKL-4 cells. In both groups as described below, transplanted Miu-i tumors were resected 3 weeks after the injections. In the treatment groups (10 mice in each group), 15 or 20 mg/kg UFF MATERIALS AND METhODS were given p.o. to the mice six times a week from 3 to 7 weeks Agents and Animals after the injections. In the control group (10 mice), the same Uracil and tegafur, provided by Taiho Pharmaceutical Co. volume of the vehicle was given in the same manner. All of the Ltd., were mixed (uracil:tegafur molar ratio of 4:1) and dis- mice were sacrificed 7 weeks after the injections. The weights of solved in 0.5% (w/v) carboxymethyl cellulose at a final tegafur the mice and right axillary lymph nodes were measured. Then, concentration of 1.5 or 2.0 mg/mi. The given dose (15 or 20 the lymph nodes and distant organs were excised, stained for mg/kg) of tegafur was expressed as that of UFT. All reagents 3-gal activity, and observed.
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