Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma.
Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 microg/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted.
Yano
Hiroki
H
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Kayukawa
Satoshi
S
Iida
Shinsuke
S
Nakagawa
Chiharu
C
Oguri
Tetsuya
T
Sanda
Takaomi
T
Ding
Jianming
J
Mori
Fumiko
F
Ito
Asahi
A
Ri
Masaki
M
Inagaki
Atsushi
A
Kusumoto
Shigeru
S
Ishida
Takashi
T
Komatsu
Hirokazu
H
Inagaki
Hiroshi
H
Suzuki
Atsushi
A
Ueda
Ryuzo
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D043182:Carboxylesterase / Q000378:metabolism*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C517204:CES2 protein, human; D043182:Carboxylesterase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
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