A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line

P. Perego, M. De Cesare, P. De Isabella, N. Carenini, G. Beggiolin, G. Pezzoni, M. Palumbo, L. Tartaglia, G. Pratesi, C. Pisano, P. Carminati, G. L. Scheffer, F. Zunino

Research output: Contribution to journalArticle

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Abstract

We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a very high degree of resistance to the selecting agent and marked resistance to topotecan and SN387 but limited resistance to doxorubicin. The development of drug resistance was independent of expression of P-glycoprotein or multidrug resistance-associated protein but was associated with high up-regulation of the breast carcinoma resistance protein (BCRP) as shown by Western blot analysis. BCRP overexpression was associated with a reduced intracellular accumulation of topotecan, a known substrate for BCRP. Conversely, a lipophilic 7-modified camptothecin analogue (ST1481) displayed a complete lack of cross-resistance in HT29/MIT cells, suggesting that the drug was not a substrate for BCRP because no defects in intracellular accumulation were found. This conclusion is consistent with the antitumor efficacy of ST1481 against a BCRP-expressing tumor. These results may have therapeutic implications because the antitumor efficacy of ST1481 is in part related to a good bioavailability after oral administration, and the drug is currently under Phase I clinical evaluation.

Original languageEnglish
Pages (from-to)6034-6037
Number of pages4
JournalCancer Research
Volume61
Issue number16
Publication statusPublished - Aug 15 2001

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Camptothecin
Mitoxantrone
Colon
Breast Neoplasms
Carcinoma
Cell Line
Topotecan
Proteins
Multidrug Resistance-Associated Proteins
HT29 Cells
P-Glycoprotein
Drug Resistance
Doxorubicin
Biological Availability
Oral Administration
Up-Regulation
Western Blotting
Pharmaceutical Preparations
ST 1481
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Perego, P., De Cesare, M., De Isabella, P., Carenini, N., Beggiolin, G., Pezzoni, G., ... Zunino, F. (2001). A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. Cancer Research, 61(16), 6034-6037.

A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. / Perego, P.; De Cesare, M.; De Isabella, P.; Carenini, N.; Beggiolin, G.; Pezzoni, G.; Palumbo, M.; Tartaglia, L.; Pratesi, G.; Pisano, C.; Carminati, P.; Scheffer, G. L.; Zunino, F.

In: Cancer Research, Vol. 61, No. 16, 15.08.2001, p. 6034-6037.

Research output: Contribution to journalArticle

Perego, P, De Cesare, M, De Isabella, P, Carenini, N, Beggiolin, G, Pezzoni, G, Palumbo, M, Tartaglia, L, Pratesi, G, Pisano, C, Carminati, P, Scheffer, GL & Zunino, F 2001, 'A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line', Cancer Research, vol. 61, no. 16, pp. 6034-6037.
Perego, P. ; De Cesare, M. ; De Isabella, P. ; Carenini, N. ; Beggiolin, G. ; Pezzoni, G. ; Palumbo, M. ; Tartaglia, L. ; Pratesi, G. ; Pisano, C. ; Carminati, P. ; Scheffer, G. L. ; Zunino, F. / A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. In: Cancer Research. 2001 ; Vol. 61, No. 16. pp. 6034-6037.
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