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===ABT-737 and navitoclax (ABT-263)===
In the mid-2000s, [[Abbott Laboratories]] developed a novel inhibitor of Bcl-2, [[Bcl-xL]] and Bcl-w, known as [[ABT-737]]. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI) that target these Bcl-2 family proteins, but not A1 or [[MCL1|Mcl-1]]. ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. ''In vitro'' studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.<ref>{{cite journal |last1=Vogler |first1=M. |last2=Dinsdale |first2=D. |last3=Dyer |first3=M. J. S. |last4=Cohen |first4=G. M. |title=Bcl-2 inhibitors: small molecules with a big impact on cancer therapy |journal=Cell Death & Differentiation |date=March 2009 |volume=16 |issue=3 |pages=360–367 |doi=10.1038/cdd.2008.137 |pmid=18806758 |s2cid=24538054 |doi-access=free |hdl=2381/4756 |hdl-access=free }}</ref> ABT-737 does not directly induce apoptosis; it enhances the effects of apoptotic signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines.{{Citation needed|reason=Claim that ABT-737 does not directly induce apoptosis is not supported|date=January 2017}}
In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.<ref>{{cite journal | vauthors = Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH | s2cid = 4335635 | display-authors = 6 | title = An inhibitor of Bcl-2 family proteins induces regression of solid tumours | journal = Nature | volume = 435 | issue = 7042 | pages = 677–81 | date = June 2005 | pmid = 15902208 | doi = 10.1038/nature03579 | bibcode = 2005Natur.435..677O }}</ref> In preclinical studies utilizing [[Patient derived tumor xenografts|patient xenografts]], ABT-737 showed efficacy for treating lymphoma and other blood cancers.<ref>{{cite journal | vauthors = Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM | title = Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer | journal = Cancer Research | volume = 68 | issue = 7 | pages = 2321–8 | date = April 2008 | pmid = 18381439 | pmc = 3159963 | doi = 10.1158/0008-5472.can-07-5031 }}</ref> Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orally [[Bioavailability|bioavailable]] derivative [[navitoclax]] (ABT-263) has similar activity on [[small cell lung cancer]] (SCLC) cell lines and has entered clinical trials.<ref name="hauck2009">{{cite journal |last1=Hauck |first1=P. |last2=Chao |first2=B. H. |last3=Litz |first3=J. |last4=Krystal |first4=G. W. |title=Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737 |journal=Molecular Cancer Therapeutics |date=1 April 2009 |volume=8 |issue=4 |pages=883–892 |doi=10.1158/1535-7163.MCT-08-1118 |pmid=19372561 |s2cid=19245418 |doi-access= }}</ref> While clinical responses with navitoclax were promising, mechanistic dose-limiting [[thrombocytopenia]] was observed in patients under treatment due to Bcl-xL inhibition in [[platelet]]s.<ref>{{cite journal | vauthors = Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM | title = Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors | journal = Journal of Clinical Oncology | volume = 29 | issue = 7 | pages = 909–16 | date = March 2011 | pmid = 21282543 | pmc = 4668282 | doi = 10.1200/JCO.2010.31.6208 }}</ref><ref>{{cite journal | vauthors = Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L | title = Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer | journal = Clinical Cancer Research | volume = 18 | issue = 11 | pages = 3163–9 | date = June 2012 | pmid = 22496272 | pmc = 3715059 | doi = 10.1158/1078-0432.CCR-11-3090 }}</ref><ref>{{cite journal | vauthors = Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H | s2cid = 10685695 | title = Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia | journal = Cancer Chemotherapy and Pharmacology | volume = 74 | issue = 3 | pages = 593–602 | date = September 2014 | pmid = 25053389 | doi = 10.1007/s00280-014-2530-9 }}</ref>
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