nach oben

Erschienen in:

01.08.2011 | Original Article

Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors

verfasst von: M. Tanioka, H. Nokihara, N. Yamamoto, Y. Yamada, K. Yamada, Y. Goto, T. Fujimoto, R. Sekiguchi, K. Uenaka, S. Callies, T. Tamura

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese.

Methods

Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week.

Results

LY2181308 was administered to 14 patients, aged 44–73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease.

Conclusions

LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.

Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921. doi:10.1038/nm0897-917 PubMedCrossRef

Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54. doi:10.1038/nrc968 PubMedCrossRef

Shen YC, Hu FC, Jeng YM, Chang YT, Lin ZZ, Chang MC, Hsu C, Cheng AL (2009) Nuclear overexpression of mitotic regulatory proteins in biliary tract cancer: correlation with clinicopathologic features and patient survival. Cancer Epidemiol Biomarkers Prev 18(2):417–423. doi:10.1158/1055-9965.EPI-08-0691 PubMedCrossRef

Carter BZ, Wang RY, Schober WD, Milella M, Chism D, Andreeff M (2003) Targeting survivin expression induces cell proliferation defect and subsequent cell death involving mitochondrial pathway in myeloid leukemic cells. Cell Cycle 2:488–493PubMedCrossRef

Ansell SM, Arendt BK, Grote DM, Jelinek DF, Novak AJ, Wellik LE, Remstein ED, Bennett CF, Fielding A (2004) Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin’s lymphoma. Leukemia 18:616–623. doi:10.1038/sj.leu.2403281 PubMedCrossRef

Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, Villa A, Marchisio PC, Altieri DC (1999) Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1:461–466PubMedCrossRef

Talbot DC, Davies J, Callies S, Andre V, Lahn M, Ang J, De Bono JS, Ranson M (2008) First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. 44th ASCO Annual Meeting

Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AA (2003) Pharmacokinetics of a tumor necrosis factor-alpha phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 31:1419–1428. doi:10.1124/dmd.31.11.1419 PubMedCrossRef

Robert J, Le Morvan V, Smith D, Pourquier P, Bonnet J (2005) Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol 54:171–196. doi:10.1016/j.critrevonc.2005.01.005 PubMedCrossRef

10.

Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K (2007) Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 46(6):1104–1110. doi:10.1016/j.jhep.2007.01.028 PubMedCrossRef

11.

Jason TL, Koropatnick J, Berg RW (2004) Toxicology of antisense therapeutics. Toxicol Appl Pharmacol 201(1):66–83. doi:10.1016/j.taap.2004.04.017 PubMedCrossRef

12.

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, version 3.0, DCTD, NCI, NIH, DHH. Publish date: December 12, 2003. Available: http://www.ctep.cancer.gov. Accessed 01 May 2010

13.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216. doi:10.1093/jnci/92.3.205 PubMedCrossRef

14.

Ryan BM, O’Donovan N, Duffy MJ (2009) Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 35:553–562. doi:10.1016/j.ctrv.2009.05.003 PubMedCrossRef

15.

Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ (1997) Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther 281:810–816PubMed

16.

Goel S, Desai K, Bulgaru A, Fields A, Goldberg G, Agrawal S, Martin R, Grindel M, Mani S (2003) A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors. Clin Cancer Res 9:4069–4076PubMed

17.

Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD (2007) Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med 204:1603–1611. doi:10.1084/jem.20062395 PubMed

18.

Rahman KM, Banerjee S, Ali S, Ahmad A, Wang Z, Kong D, Sakr WA (2009) 3, 3′-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. Cancer Res 69:4468–4475. doi:10.1158/0008-5472.CAN-08-4423 PubMedCrossRef

19.

Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, Meng L, Wang S, Lu Y, Ma D (2008) Activation of fibronectin/PI-3 K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett 261:108–119. doi:10.1016/j.canlet.2007.11.022 PubMedCrossRef

20.

Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F, Daidone MG (2002) Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci 59:1406–1412. doi:10.1007/s00018-002-8518-3 PubMedCrossRef

21.

Rödel F, Frey B, Leitmann W, Capalbo G, Weiss C, Rödel C (2008) Survivin antisense oligonucleotides effectively radiosensitize colorectal cancer cells in both tissue culture and murine xenograft models. Int J Radiat Oncol Biol Phys 71:247–255. doi:10.1016/j.ijrobp.2008.02.011 PubMedCrossRef

22.

Nokihara H, Yamamoto N, Yamada Y, Yamada K, Goto Y, Tanioka M, Nambu Y, Uenaka K, Sekiguchi R, Tamura T (2009) A phase 1 study of an antisense oligonucleotide against survivin (LY2181308) in Japanese patients with solid tumors. Mol Cancer Ther 8:B48. doi:10.1158/1535-7163.TARG-09-B48

Titel: Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors
verfasst von: M. Tanioka
H. Nokihara
N. Yamamoto
Y. Yamada
K. Yamada
Y. Goto
T. Fujimoto
R. Sekiguchi
K. Uenaka
S. Callies
T. Tamura
Publikationsdatum: 01.08.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1506-7

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Phase I study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors