Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model.

Mamoru Nukatsuka, Akio Fujioka, Fumio Nakagawa, Hideyuki Oshimo, Kenji Kitazato, Jyunji Uchida, Yoshikazu Sugimoto, Sekio Nagayama, Masakazu Fukushima

Research output: Contribution to journalArticle

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Abstract

To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41%, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94%, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.

Original languageEnglish
Pages (from-to)1531-1536
Number of pages6
JournalInternational Journal of Oncology
Volume25
Issue number6
Publication statusPublished - 2004 Dec
Externally publishedYes

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Dihydrouracil Dehydrogenase (NADP)
Paclitaxel
Breast Neoplasms
Neoplasms
Fluorouracil
Lung
Neoplasm Metastasis
Taxoids
SCID Mice
Prodrugs
Growth
Heterografts
Adipose Tissue
Breast

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model. / Nukatsuka, Mamoru; Fujioka, Akio; Nakagawa, Fumio; Oshimo, Hideyuki; Kitazato, Kenji; Uchida, Jyunji; Sugimoto, Yoshikazu; Nagayama, Sekio; Fukushima, Masakazu.

In: International Journal of Oncology, Vol. 25, No. 6, 12.2004, p. 1531-1536.

Research output: Contribution to journalArticle

Nukatsuka, Mamoru ; Fujioka, Akio ; Nakagawa, Fumio ; Oshimo, Hideyuki ; Kitazato, Kenji ; Uchida, Jyunji ; Sugimoto, Yoshikazu ; Nagayama, Sekio ; Fukushima, Masakazu. / Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model. In: International Journal of Oncology. 2004 ; Vol. 25, No. 6. pp. 1531-1536.
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abstract = "To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41{\%}, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94{\%}, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.",
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AU - Nukatsuka, Mamoru

AU - Fujioka, Akio

AU - Nakagawa, Fumio

AU - Oshimo, Hideyuki

AU - Kitazato, Kenji

AU - Uchida, Jyunji

AU - Sugimoto, Yoshikazu

AU - Nagayama, Sekio

AU - Fukushima, Masakazu

PY - 2004/12

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