A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line.
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 SN38, 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.
Perego
P
P
Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy. perego@istitutotumori.mi.it
De Cesare
M
M
De Isabella
P
P
Carenini
N
N
Beggiolin
G
G
Pezzoni
G
G
Palumbo
M
M
Tartaglia
L
L
Pratesi
G
G
Pisano
C
C
Carminati
P
P
Scheffer
G L
GL
Zunino
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004249:DNA Damage; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D019073:HT29 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019772:Topotecan; C116614:ABCG2 protein, human; C433984:ST 1481