Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: Determination of efficacy and possible mechanisms of resistance

Hattum, Annemarie H. Van; Schlüper, Hennie M.M.; Hausheer, Frederick H.; Pinedo, H.M.; Boven, Epie

doi:10.1002/ijc.10434

Cited by 40 publications

(24 citation statements)

References 17 publications

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“…33 Another camptothecin analogue, karenitecin (BNP1350), is not an ABCG2 substrate. 34 Other studies have identified modifications of the camptothecin parent structure which abolish ABCG2-mediated efflux. 35 9-Nitrocamptothecin has intermediate affinity for…”

Section: Topoisomerase Inhibitiorsmentioning

confidence: 99%

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells

Abbott

2003

Hematological Oncology

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ABCG2 (BCRP) is a member of the ATP-binding cassette (ABC) family of cell surface transport proteins. ABCG2 expression occurs in a variety of normal tissues, and is relatively limited to primitive stem cells. ABCG2 expression is associated with the side population (SP) phenotype of Hoechst 33342 efflux. The substrate profile of ABCG2 includes the antineoplastic drugs primarily targeting topoisomerases, including anthracyclines and camptothecins. More recently, pheophorbide, a chlorophyll-breakdown product, and protoporhyrin IX have been described as ABCG2 substrates, perhaps indicating a physiologic role of cytoprotection of primitive cells. Also, mice lacking ABCG2 expression have no intrinsic stem cell defects, although there is a remarkable increase in toxicity with antineoplastic drugs that are ABCG2 substrates, and also a photosensitivity resembling protoporphyria. Like other members of the ABC family, such as MDR1 and MRP1, ABCG2 is expressed in a variety of malignancies. Despite numerous reports of ABCG2 expression in AML, there is little evidence that ABCG2 expression is correlated with an adverse clinical outcome. This review will focus on the potential usefulness of ABCG2 as a marker primitive stem cells and possible physiologic roles of ABCG2 in protection of primitive stem cell populations, and potential methods of overcoming ABCG2-associated drug resistance in anticancer therapy.

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Section: Topoisomerase Inhibitiorsmentioning

confidence: 99%

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells

Abbott

2003

Hematological Oncology

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“…Cancer cells that express BCRP are not resistant to camptothecin itself, or to the camptothecin analogs BNP1350, DX8951f, or NX211 (Ishii et al, 2000;Maliepaard et al, 2001b;Van Hattum et al, 2001;Van Hattum et al, 2002). Studies of SN-38-and irinotecan-resistant PC-6 sublines, which overexpress BCRP, also demonstrated that these cells were not resistant to the clinically promising water-soluble camptothecin analog DX-8951f (Ishii et al, 2000).…”

Section: Resistance To Topoisomerase I Inhibitorsmentioning

confidence: 99%

“…Kruijtzer et al (2002) also demonstrated evidence for decreased biliary and renal excretion of topotecan by GF120918 by showing that the drug reduces plasma clearance of topotecan administered intravenously. Newer camptothecin derivatives such as BNP1350, likely owe their superior oral bioavailability to the fact that they are poor substrates for BCRP (Van Hattum et al, 2002). …”

Section: Bcrp Effects On Drug Bioavailability Pharmacokineticsmentioning

confidence: 99%

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

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“…Selection with mitoxantrone [68], topotecan [69,70] or SN-38 [71] results in ABCG2 overexpression as does selection with flavopiridol [72]. Even selection with DX-8951f or BNP-1350, camptothecins that are relatively poor ABCG2 substrates, results in ABCG2 upregulation [73,74]. Indolocarbazole topoisomerase I inhibitors J-107088 and NB-506 [75] have been shown to be transported by ABCG2, as have the tyrosine kinase inhibitors CI1033 [76], gefitinib [77], and imatinib [78].…”

Section: Substrates Of Abcg2mentioning

confidence: 99%

ABCG2: determining its relevance in clinical drug resistance

Robey

Polgár

Deeken

et al. 2007

Cancer Metastasis Rev

341

267

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Multidrug resistance is a major obstacle to successful cancer treatment. One mechanism by which cells can become resistant to chemotherapy is the expression of ABC transporters that use the energy of ATP hydrolysis to transport a wide variety of substrates across the cell membrane. There are three human ABC transporters primarily associated with the multidrug resistance phenomenon, namely Pgp, MRP1, and ABCG2. All three have broad and, to a certain extent, overlapping substrate specificities, transporting the major drugs currently used in cancer chemotherapy. ABCG2 is the most recently described of the three major multidrug-resistance pumps, and its substrates include mitoxantrone, topotecan, irinotecan, flavopiridol, and methotrexate. Despite several studies reporting ABCG2 expression in normal and malignant tissues, no trials have thus far addressed the role of ABCG2 in clinical drug resistance. This gives us an opportunity to critically review the disappointing results of past clinical trials targeting Pgp and to propose strategies for ABCG2. We need to know in which tumor types ABCG2 contributes to the resistance phenotype. We also need to develop standardized assays to detect ABCG2 expression in vivo and to carefully select the chemotherapeutic agents and clinical trial designs. This review focuses on our current knowledge about normal tissue distrubution, tumor expression profiles, and substrates and inhibitors of ABCG2, together with lessons learned from clinical trials with Pgp inhibitors. Implications of SNPs in the ABCG2 gene affecting the pharmacokinetics of substrate drugs, including many non-chemotherapy agents and ABCG2 expression in the SP population of stem cells are also discussed.

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Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: Determination of efficacy and possible mechanisms of resistance

Cited by 40 publications

References 17 publications

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

ABCG2: determining its relevance in clinical drug resistance

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