The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity
Open accessAbstract
Background Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.Methods In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.Findings 55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218).Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.Funding Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Drugs with single or limited targets, such as Nutlin3a (an MDM2 inhibitor) or navitoclax (a BCL-2 inhibitor), can have off-target apoptotic effects on multiple non-Snc types, such as neutrophils and platelets in the case of navitoclax (75), making them panolytic.”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [75]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“N can cause thrombocytopenia and neutropenia, even after brief exposures57,88–91”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [89]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these agents exhibited notable drawbacks, such as dose-dependent thrombocytopenia, variable therapeutic efficacy, and the emergence of resistance mechanisms.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Trials assessing navitoclax as an anticancer agent report neutropenia and thrombocytopenia (Wilson et al. 2010).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wilson et al. 2010
In the citing paper
“However, chronic administration of at least some senolytics in humans can be associated with toxic side effects (Kaefer et al., 2014; Wilson et al., 2010) which may be due to off-target killing of non-senescent cells.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Wilson et al., 2010
In the citing paper
“In oncology trials, 44–50% of patients experienced grade 3 or 4 thrombocytopenia33,34.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,239
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1958) · Journal of the American Statistical Association · doi:10.1080/01621459.1958.10501452 · Cited by 39,158
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
Swerdlow, S. H. (2017) · Medical Entomology and Zoology · Cited by 12,933
Danial, N. N., & Korsmeyer, S. J. (2004) · Cell · doi:10.1016/s0092-8674(04)00046-7 · Cited by 4,651
Hallek, M. J., Cheson, B. D., Catovsky, D., Caligaris‐Cappio, F., Dighiero, G., Döhner, H., Hillmen, P., Keating, M. J., Montserrat, E., Rai, K. R., et al. (2008) · Blood · doi:10.1182/blood-2007-06-093906 · Cited by 3,782
Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death
Hockenbery, D., Nuñez, G., Milliman, C., Schreiber, R. D., & Korsmeyer, S. J. (1990) · Nature · doi:10.1038/348334a0 · Cited by 3,720
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,407
Self-citationCheson, B. D., Horning, S., Coiffier, B., Shipp, M., Fisher, R. I., Connors, J. M., Lister, T., Vose, J., Grillo-López, A., Hagenbeek, A., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.4.1244 · Cited by 3,210
A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia
Calin, G. A., Ferracin, M., Cimmino, A., Leva, G. D., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. İ., Fabbri, M., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050995 · Cited by 2,415
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5836 · Cited by 1,992
Self-citation
Cited by
Sorted by citations
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3048 · Cited by 3,058
Self-citationTargeting apoptosis in cancer therapy
Carneiro, B. A., & El‐Deiry, W. S. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0341-y · Cited by 2,676
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Roberts, A. W., Davids, M. S., Pagel, J. M., Kahl, B. S., Puvvada, S. D., Gerecitano, J. F., Kipps, T. J., Anderson, M. A., Brown, J. R., Gressick, L. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1513257 · Cited by 1,930
“No chromosome 17p or 11q deletion 16/49 (33) 27/53 (51) 43/102 (42)”
Self-citationCellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
Senolytic drugs: from discovery to translation
Kirkland, J. L., & Tchkonia, T. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13141 · Cited by 1,227
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177
“Trials assessing navitoclax as an anticancer agent report neutropenia and thrombocytopenia (Wilson et al. 2010).”
BackgroundCellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,134
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., Chanrion, M., Kelly, G. L., Gong, J.-N., Moujalled, D. M., et al. (2016) · Nature · doi:10.1038/nature19830 · Cited by 1,047
From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors
Ashkenazi, A., Fairbrother, W. J., Leverson, J. D., & Souers, A. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.253 · Cited by 903
Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics
Jan, R., & Chaudhry, G.-E.-S. (2019) · Advanced Pharmaceutical Bulletin · doi:10.15171/apb.2019.024 · Cited by 957
Roberts, A. W., Seymour, J. F., Brown, J. R., Wierda, W. G., Kipps, T. J., Khaw, S. L., Carney, D. A., He, S., Huang, D. C. S., Xiong, H., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.34.7898 · Cited by 855
Self-citationSystems biology of cisplatin resistance: past, present and future
Galluzzi, L., Vitale, I., Michels, J., Brenner, C., Szabadkai, G., Harel-Bellan, A., Castedo, M., & Kroemer, G. (2014) · Cell Death & Disease · doi:10.1038/cddis.2013.428 · Cited by 782
Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies
Delbridge, A. R. D., Grabow, S., Strasser, A., & Vaux, D. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.17 · Cited by 752
Davids, M. S., Roberts, A. W., Seymour, J. F., Pagel, J. M., Kahl, B. S., Wierda, W. G., Puvvada, S. D., Kipps, T. J., Anderson, M. A., Salem, A. H., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.4320 · Cited by 746
“Emergent* Any event 103 (97) 21 (96) 33 (100) 49 (96) 59 (56) 14 (64) 21 (64) 24 (47) Nausea 51 (48) 9 (41) 15 (45) 27 (53) 0 0 0 0 Diarrhea 48 (45) 7 (32) 14 (42) 27 (53) 3 (3) 0 2 (6) 1 (2) Fatigue 44 (42) 10 (45) 9 (27) 25 (49) 7 (7) 2 (9) 2 (6) 3 (6) Decreased appetite 23 (22) 4 (18) 4 (12) 15 (29) 1 (1) 0 0 1 (2)”
BackgroundInfluentialSelf-citationBCL-2 family isoforms in apoptosis and cancer
Warren, C., Wong‐Brown, M. W., & Bowden, N. A. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1407-6 · Cited by 717
The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update
Siddiqui, W. A., Ahad, A., & Ahsan, H. (2015) · Archives of Toxicology · doi:10.1007/s00204-014-1448-7 · Cited by 703
Targeting senescent cells alleviates obesity-induced metabolic dysfunction
Palmer, A. K., Xu, M., Zhu, Y., Pirtskhalava, T., Weivoda, M. M., Hachfeld, C. M., Prata, L. G., van Dijk, T. H., Verkade, E., Casaclang‐Verzosa, G., et al. (2019) · Aging Cell · doi:10.1111/acel.12950 · Cited by 658
“(d) Navitoclax and other BCL‐2 family member inhibitors can be toxic, for example, causing severe thrombocytopenia, which can occur even with intermittent dosing (Wilson et al., 2010).”
BackgroundLeverson, J. D., Phillips, D. C., Mitten, M. J., Boghaert, E. R., Diaz, D., Tahir, S. K., Belmont, L. D., Nimmer, P., Xiao, Y., Ma, X. M., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4642 · Cited by 541
“This is in contrast to the single-agent setting, where MTDs of 315 or 325 mg/day were achieved before thrombocytopenia became dose-limiting (11, 31).”
BackgroundMethodResultInfluentialSelf-citationThe BCL-2 arbiters of apoptosis and their growing role as cancer targets
Adams, J. M., & Cory, S. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.161 · Cited by 530
“Because BCL-XL controls platelet lifespan, 74 ABT-737 and navitoclax provoke acute dose-limiting thrombocytopaenia.(75,76) Efforts to circumvent this problem led to the development of the BCL-2-specific venetoclax (ABT-199)(73) that spares platelets.”
BackgroundTargeting BCL-2 regulated apoptosis in cancer
Campbell, K. J., & Tait, S. W. G. (2018) · Open Biology · doi:10.1098/rsob.180002 · Cited by 564
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501
BCL-2 protein family: attractive targets for cancer therapy
Kaloni, D., Diepstraten, S. T., Strasser, A., & Kelly, G. L. (2022) · APOPTOSIS · doi:10.1007/s10495-022-01780-7 · Cited by 547
Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Friedberg, J. W. (2011) · Hematology · doi:10.1182/asheducation-2011.1.498 · Cited by 499
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.006 · Cited by 469
Strategies for optimizing the response of cancer and normal tissues to radiation
Moding, E. J., Kastan, M. B., & Kirsch, D. G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4003 · Cited by 474
Pathogenesis of Human B Cell Lymphomas
Shaffer, A. L., Young, R. M., & Staudt, L. M. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075027 · Cited by 457
The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy
Vogler, M., Braun, Y., Smith, V. M., Westhoff, M.-A., Pereira, R. S., Pieper, N. M., Anders, M., Callens, M., Vervliet, T., Abbas, M., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02176-0 · Cited by 462
“277,279,282 Consequently, many trials involving single-agent navitoclax have been completed/withdrawn.”
Diffuse large B-cell lymphoma—treatment approaches in the molecular era
Roschewski, M. J., Staudt, L. M., & Wilson, W. H. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.197 · Cited by 436
Self-citationRamsey, H. E., Fischer, M. A., Lee, T., Gorska, A. E., Arrate, M. P., Fuller, L., Boyd, K. L., Strickland, S. A., Sensintaffar, J., Hogdal, L. J., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0140 · Cited by 385
Molecular pathogenesis of mantle cell lymphoma
Jares, P., Colomer, D., & Campo, E. (2012) · Journal of Clinical Investigation · doi:10.1172/jci61272 · Cited by 398
“use of proapoptotic molecules that mimic the activity of BH3-only proteins (105) has shown promising Results in preclinical models (106–108) but no responses or only modest activity in clinical studies (82, 109).”
Structure-guided design of a selective BCL-XL inhibitor
Lessène, G., Czabotar, P. E., Sleebs, B. E., Zobel, K., Lowes, K. N., Adams, J. M., Baell, J. B., Colman, P. M., Deshayes, K., Fairbrother, W. J., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1246 · Cited by 393
Griner, L. A. M., Guha, R., Shinn, P., Young, R. M., Keller, J. M., Liu, D., Goldlust, I. S., Yasgar, A., McKnight, C. G., Boxer, M. B., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311846111 · Cited by 387
“The present study demonstrates a favorable interaction between ibrutinib and the BCL2 family antagonists navitoclax and ABT-199, which have yielded single-agent activity in B-cell malignancies (51).”
BackgroundCardiac glycosides are broad-spectrum senolytics
Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0122-z · Cited by 359
Schoenwaelder, S. M., Jarman, K. E., Gardiner, E. E., Hua, M., Qiao, J., White, M. J., Josefsson, E. C., Alwis, I., Ono, A., Willcox, A., et al. (2011) · Blood · doi:10.1182/blood-2011-04-347849 · Cited by 351
The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs
Diepstraten, S. T., Anderson, M. A., Czabotar, P. E., Lessène, G., Strasser, A., & Kelly, G. L. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00407-4 · Cited by 351
Vo, T.-T. T., Ryan, J. A., Carrasco, R. D., Neuberg, D. S., Rossi, D. J., Stone, R. M., DeAngelo, D. J., Frattini, M. G., & Letai, A. G. (2012) · Cell · doi:10.1016/j.cell.2012.08.038 · Cited by 356
“However, ABT-199 has greater selectivity for BCL-2 and lower affinity for BCL-XL, so the chances are better for achieving in vivo BCL-2 antagonism without exacerbating thrombocytopenia.”
The Use of Therapeutic Peptides to Target and to Kill Cancer Cells
Boohaker, R. J., Lee, M. W., Vishnubhotla, P., Perez, J. L. M., & Khaled, A. R. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712801661004 · Cited by 342
“In clinical trials, navitoclax demonstrated toxicity against selected hematological malignancies [83, 84].”
BackgroundSenolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Robbins, P. D., Jurk, D., Khosla, S., Kirkland, J. L., LeBrasseur, N. K., Miller, J. D., Passos, J. F., Pignolo, R. J., Tchkonia, T., & Niedernhofer, L. J. (2021) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-050120-105018 · Cited by 360
“Drugs with single or limited targets, such as Nutlin3a (an MDM2 inhibitor) or navitoclax (a BCL-2 inhibitor), can have off-target apoptotic effects on multiple non-Snc types, such as neutrophils and platelets in the case of navitoclax (75), making them panolytic.”
BackgroundVenetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study
Seymour, J. F., Ma, S., Brander, D. M., Choi, M. Y., Barrientos, J. C., Davids, M. S., Anderson, M. A., Beaven, A., Rosen, S. T., Tam, C. S. L., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30012-8 · Cited by 333
Self-citationMitochondria-mediated oxidative stress during viral infection
Foo, J., Bellot, G. L., Pervaiz, S., & Alonso, S. (2022) · Trends in Microbiology · doi:10.1016/j.tim.2021.12.011 · Cited by 328
Why do BCL-2 inhibitors work and where should we use them in the clinic?
Montero, J., & Letai, A. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.183 · Cited by 335
Discovery of a Potent and Selective BCL-X L Inhibitor with in Vivo Activity
Tao, Z., Hasvold, L. A., Wang, L., Wang, X., Petros, A. M., Park, C. H., Boghaert, E. R., Catron, N. D., Chen, J., Colman, P. M., et al. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml5001867 · Cited by 311
Self-citationPathways and mechanisms of venetoclax resistance
Bose, P., Gandhi, V. V., & Konopleva, M. Y. (2017) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2017.1283032 · Cited by 311
Pullarkat, V. A., Lacayo, N. J., Jabbour, E. J., Rubnitz, J. E., Bajel, A. R., Laetsch, T. W., Leonard, J. T., Colace, S. I., Khaw, S. L., Fleming, S. A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1465 · Cited by 309
Self-citationGonzález‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson, J. R., González‐López, C., Ou, H., Mirón‐Barroso, S., Zhang, Z., Lérida‐Viso, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13142 · Cited by 303
“In addition to thrombocytopenia, the first trial to evaluate Navitoclax in lymphoid malignancies resulted in grade III transaminitis and gastrointestinal bleed in a proportion of patients subjected to a continuous dosing schedule (Wilson et al., 2010).”
BackgroundCytoplasmic DNA: sources, sensing, and role in aging and disease
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D. (2021) · Cell · doi:10.1016/j.cell.2021.09.034 · Cited by 288
BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines
Mérino, D., Kelly, G. L., Lessène, G., Wei, A. H., Roberts, A. W., & Strasser, A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.11.004 · Cited by 300
ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development
Cang, S., Iragavarapu, C., Savooji, J., Song, Y., & Liu, D. (2015) · Journal of Hematology & Oncology · doi:10.1186/s13045-015-0224-3 · Cited by 289
“In the continuous-schedule regimen, grade III transaminitis and gastrointestinal bleed were observed [59].”
BackgroundModulators of 14-3-3 Protein–Protein Interactions
Stevers, L. M., Sijbesma, E., Botta, M., MacKintosh, C., Obšil, T., Landrieu, I., Cau, Y., Wilson, A. J., Karawajczyk, A., Eickhoff, J., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00574 · Cited by 295
Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand?
Baig, S., Seevasant, I., Mohamad, J., Mukheem, A., Huri, H. Z., & Kamarul, T. (2016) · Cell Death and Disease · doi:10.1038/cddis.2015.275 · Cited by 292
IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis
Faust, H. J., Zhang, H., Han, J., Wolf, M. T., Jeon, O. H., Sadtler, K., Peña, A. N., Chung, L., Maestas, D. R., Tam, A. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134091 · Cited by 260
“Thrombocytopenia had a dose-limiting effect in clinical trials, though neutropenia and a reduction in circulating lymphocytes were also observed (53), consistent with the role of these pathways in lymphocyte maturation (54).”
BackgroundTargeting the B-Cell Lymphoma/Leukemia 2 Family in Cancer
Davids, M. S., & Letai, A. G. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.37.0981 · Cited by 260
“In a phase I single-agent trial in relapsed or refractory lymphoid malignancies, 10 of 46 evaluable patients had a partial response.(55) Patients with CLL/small lymphocytic lymphoma received disproportionate benefit, with eight of 16 achieving a partial response and 13 of 16 showing reduction in tumor size.”
BackgroundCancer stem cells – important players in tumor therapy resistance
Çolak, S., & Medema, J. P. (2014) · FEBS Journal · doi:10.1111/febs.13023 · Cited by 260
Classification of mitocans, anti-cancer drugs acting on mitochondria
Neužil, J., Dong, L., Rohlena, J., Truksa, J., & Ralph, S. J. (2012) · Mitochondrion · doi:10.1016/j.mito.2012.07.112 · Cited by 255
Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives
Hafezi, S., & Rahmani, M. (2021) · Cancers · doi:10.3390/cancers13061292 · Cited by 248
“In addition, phase I clinical trials conducted in patients with non-small cell lung cancer (NSCLC) or lymphoid malignancies [32,33] have shown that navitoclax is safe and well tolerated; however a dose-dependent thrombocytopenia, a consequence of BCL-XL inhibition [34], was a major adverse effect.”
BackgroundJurinović, V., Kridel, R., Staiger, A. M., Szczepanowski, M., Horn, H., Dreyling, M. H., Rosenwald, A., Ott, G., Klapper, W., Zelenetz, A. D., et al. (2016) · Blood · doi:10.1182/blood-2016-05-717355 · Cited by 233
Bond, M. J., & Crews, C. M. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00011j · Cited by 232
Decoding and unlocking the BCL-2 dependency of cancer cells
Juin, P. P., Geneste, O., Gautier, F., Depil, S., & Campone, M. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3538 · Cited by 254
BCL-2 as therapeutic target for hematological malignancies
Perini, G. F., Ribeiro, G., Neto, J. V. P., Campos, L. T., & Hamerschlak, N. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0608-2 · Cited by 227
“Responses were detected in distinct tumor types, with partial response being observed in 10 of 46 evaluable patients [47].”
BackgroundTargeting the apoptosis pathway in hematologic malignancies
Zaman, S., Wang, R., & Gandhi, V. V. (2013) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2013.855307 · Cited by 231
“Two phase I studies in lymphoid malignancies have been conducted and reported [74,75].”
Staiger, A. M., Ziepert, M., Horn, H., Scott, D. W., Barth, T. F. E., Bernd, H., Feller, A. C., Klapper, W., Szczepanowski, M., Hummel, M., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.3660 · Cited by 225
BH3 Mimetics: Status of the Field and New Developments
Billard, C. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0058 · Cited by 229
The Mitochondrion as an Emerging Therapeutic Target in Cancer
Roth, K. G., Mambetsariev, I., Kulkarni, P., & Salgia, R. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.06.009 · Cited by 219
Regulation of Bim in Health and Disease
Sionov, R. V., Vlahopoulos, S., & Granot, Z. (2015) · Oncotarget · doi:10.18632/oncotarget.5492 · Cited by 233
“ABT-263 (Navitoclax) is a clinical derivative of ABT-737 that are currently undergoing phase I and II clinical evaluation in various tumor types including leukemia [580-582].”
BackgroundBogenberger, J. M., Kornblau, S. M., Pierceall, W. E., Lena, R. J., Chow, D. C., Shi, C.-X., Mantei, J., Ahmann, G. J., Gonzales, I. M., Choudhary, A. K., et al. (2014) · Leukemia · doi:10.1038/leu.2014.44 · Cited by 199
BCL2 and MCL1 inhibitors for hematologic malignancies
Roberts, A. W., Wei, A. H., & Huang, D. C. S. (2021) · Blood · doi:10.1182/blood.2020006785 · Cited by 211
Vogler, M., Hamali, H. A., Sun, X.-M., Bampton, E. T. W., Dinsdale, D. D., Snowden, R. T., Dyer, M. J. S., Goodall, A. H., & Cohen, G. M. (2011) · Blood · doi:10.1182/blood-2011-03-344812 · Cited by 198
Potential mechanisms of resistance to venetoclax and strategies to circumvent it
Tahir, S. K., Smith, M. L., Hessler, P., Rapp, L., Idler, K. B., Park, C. H., Leverson, J. D., & Lam, L. T. (2017) · BMC Cancer · doi:10.1186/s12885-017-3383-5 · Cited by 197
Kipps, T. J., Eradat, H. A., Grosicki, S., Catalano, J. V., Cosolo, W., Dyagil, I., Yalamanchili, S., Chai, A., Sahasranaman, S., Punnoose, E. A., et al. (2015) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1030638 · Cited by 196
Vandenberg, C. J., & Cory, S. (2013) · Blood · doi:10.1182/blood-2013-01-475855 · Cited by 194
Mérino, D., Khaw, S. L., Glaser, S. P., Anderson, D. J., Belmont, L. D., Wong, C., Yue, P., Robati, M., Phipson, B., Fairlie, W. D., et al. (2012) · Blood · doi:10.1182/blood-2011-12-400929 · Cited by 199
BH3-only proteins in apoptosis at a glance
Happo, L., Strasser, A., & Cory, S. (2012) · Journal of Cell Science · doi:10.1242/jcs.090514 · Cited by 200
“ABT-263, currently in early Phase I–II clinical trials, has shown promising efficacy in chronic lymphocytic leukaemia (CLL) patients (Gandhi et al., 2011; Tse et al., 2008; Wilson et al., 2010).”
BackgroundSmall molecule inhibitors targeting the cancers
Liu, G., Chen, T., Zhang, X., Ma, X., & Shi, H. (2022) · MedComm · doi:10.1002/mco2.181 · Cited by 212
Josefsson, E. C., James, C., Henley, K. J., Debrincat, M. A., Rogers, K. L., Dowling, M. R., White, M. J., Kruse, E., Lane, R. M., Ellis, S. L., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110750 · Cited by 192
Saleh, T., Carpenter, V. J., Tyutyunyk‐Massey, L., Murray, G., Leverson, J. D., Souers, A. J., Alotaibi, M. R., Faber, A. C., Reed, J., Harada, H., et al. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12761 · Cited by 190
Anti-senescence compounds: A potential nutraceutical approach to healthy aging
Gurău, F., Baldoni, S., Prattichizzo, F., Espinosa, E., Amenta, F., Procopio, A. D., Albertini, M. C., Bonafè, M., & Olivieri, F. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.05.001 · Cited by 179
“Thrombocytopenia is due Bcl-xl inhibition, which results in reduced platelet lifespan (Wilson et al., 2010; Gandhi et al., 2011; Xiong et al., 2014).”
Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax
Anderson, M. A., Tam, C. S. L., Lew, T. E., Juneja, S. K., Juneja, M., Westerman, D., Wall, M., Lade, S., Gorelik, A., Huang, D. C. S., et al. (2017) · Blood · doi:10.1182/blood-2017-01-763003 · Cited by 176
“Number (N) 67 42 3 14 8 Age, y, median (range) 68 (20-87) 68 (20-87) 62 (54-73) 62 (47-74) 70 (65-78) Prior therapies, median (range) 3 (1-12) 3 (1-12) 2 (1-3) 4 (2-8) 4 (1-7) F-refractory, n (n/N%) 33 (49) 16 (38) 2 (67) 8 (57) 7 (88) Bulky disease, n (n/N%) 32 (48) 16 (38) 1 (33) 10 (71) 5 (63) Venetoclax ,400 mg/d,…”
Targeting Apoptosis Pathways for New Cancer Therapeutics
Bai, L., & Wang, S. (2013) · Annual Review of Medicine · doi:10.1146/annurev-med-010713-141310 · Cited by 179
“Several clinical trials of ABT-263 have been conducted in patients with chronic lymphocytic leukemia (CLL) (23), lymphoma (24), and lung cancer (25).”
BackgroundWalensky, L. D., & Gavathiotis, E. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.08.009 · Cited by 173
Cellular senescence in the aging and diseased kidney
Valentijn, F. A., Falke, L. L., Nguyen, T. Q., & Goldschmeding, R. (2018) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-017-0434-2 · Cited by 173
“For instance, navitoclax caused dosedependent thrombocytopenia, due to inhibition of BCL-X in platelets resulting in platelet apoptosis (Mason et al. 2007; Zhang et al. 2007; Wilson et al. 2010).”
BackgroundClinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent
Anuar, N. N. M., Hisam, N. S. N., Liew, S. L., & Ugusman, A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.564108 · Cited by 177
“They reported a novel pharmacodynamic effect of navitoclax on peripheral thrombocytopenia and T-cell lymphopenia in treating lymphoid tumors owing to high affinity inhibitions of BCL-2 and BCL-XL proteins (Wilson et al., 2010).”
BackgroundMethodInfluentialDirect and selective small-molecule activation of proapoptotic BAX
Gavathiotis, E., Reyna, D. E., Bellairs, J. A., Leshchiner, E. S., & Walensky, L. D. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.995 · Cited by 171
Control of cell death and mitochondrial fission by ERK 1/2 MAP kinase signalling
Cook, S. J., Stuart, K., Gilley, R., & Sale, M. J. (2017) · FEBS Journal · doi:10.1111/febs.14122 · Cited by 176
The Bcl-2 family: structures, interactions and targets for drug discovery
Kvansakul, M., & Hinds, M. G. (2014) · APOPTOSIS · doi:10.1007/s10495-014-1051-7 · Cited by 171
Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas
Sarkozy, C., Traverse‐Glehen, A., & Coiffier, B. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00005-4 · Cited by 168
Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment
Correia, C., Lee, S. H., Meng, X. W., Vincelette, N. D., Knorr, K. L. B., Ding, H., Nowakowski, G. S., Dai, H., & Kaufmann, S. H. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.03.012 · Cited by 172
Letai, A. G. (2016) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050216-121933 · Cited by 172
“…in several clinical trials, with mixed efficacy in CLL, small-cell lung cancer, and other solid tumors (Gandhi et al. 2011, Roberts et al. 2012, Wilson et al. 2010) An on-target toxicity of thrombocytopenia based on the BCL-XL dependence of mature circulating platelets limited dose escalation…”
BackgroundKaefer, A., Yang, J., Noertersheuser, P., Mensing, S., Humerickhouse, R., Awni, W., & Xiong, H. (2014) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-014-2530-9 · Cited by 161
Self-citationTargeting oncogene and non-oncogene addiction to inflame the tumour microenvironment
Petroni, G., Buqué, A., Coussens, L. M., & Galluzzi, L. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00415-5 · Cited by 162
Direct activation of full-length proapoptotic BAK
Leshchiner, E. S., Braun, C. R., Bird, G. H., & Walensky, L. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214313110 · Cited by 157
“For example, bacterial expression and purification of antiapoptotic BCL-XL, with the C terminus removed and an unstructured loop trimmed, led to a fundamental understanding of how BCL-2 survival proteins trap the BH3 helices of proapoptotic proteins to block cell death (10, 42) and provided a blueprint for the develop…”
BackgroundTurning back time with emerging rejuvenation strategies
Mahmoudi, S., Xu, L., & Brunet, A. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0206-0 · Cited by 171
Targeting the Bcl-2 Family in B Cell Lymphoma
Adams, C. M., Clark-Garvey, S., Porcu, P., & Eischen, C. M. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2018.00636 · Cited by 163
Cancer therapeutics: Targeting the apoptotic pathway
Khan, K. H., Blanco-Codesido, M., & Molife, L. R. (2013) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2013.12.012 · Cited by 164
“A first dose escalation study in 5 patients with relapsed or refractory lymphoid malignanies highlighted the key side effects of thrombocytopenia, eutropenia, fatigue and gastrointestinal disturbance [155] Table 2).”
BackgroundInfluentialRahmani, M., Aust, M. M., Attkisson, E., Williams, D. C., Ferreira‐Gonzalez, A., & Grant, S. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1365 · Cited by 157
D’Aguanno, S., & Bufalo, D. D. (2020) · Cells · doi:10.3390/cells9051287 · Cited by 158
Targeting BCL-2-like Proteins to Kill Cancer Cells
Cory, S., Roberts, A. W., Colman, P. M., & Adams, J. M. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.07.001 · Cited by 148
Targeting BCL2 for the Treatment of Lymphoid Malignancies
Anderson, M. A., Huang, D. C. S., & Roberts, A. W. (2014) · Seminars in Hematology · doi:10.1053/j.seminhematol.2014.05.008 · Cited by 150
Roberts, A. W., & Huang, D. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.553 · Cited by 153
Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
Rahmani, M., Nkwocha, J., Hawkins, E., Pei, X., Parker, R. E., Kmieciak, M., Leverson, J. D., Sampath, D., Ferreira‐Gonzalez, A., & Grant, S. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3024 · Cited by 147
“Although ABT-263was well tolerated and showed activity in patients with various hematologic malignancies, a limitation has been thrombocytopenia (4–6), reflecting effects of BCL-XL inhibition on platelet survival (4, 7).”
BackgroundSonpavde, G., Matveev, V. B., Burke, J. M., Caton, J. R., Fleming, M. T., Hutson, T. E., Galsky, M. D., Berry, W. R., Karlov, P., Holmlund, J., et al. (2011) · Annals of Oncology · doi:10.1093/annonc/mdr555 · Cited by 149
Metadata
- Authors
- Wilson, W. H., O'Connor, O. A., Czuczman, M. S., LaCasce, A. S., Gerecitano, J. F., Leonard, J. P., Tulpule, A., Dunleavy, K., Xiong, H., Chiu, Y.-L., Cui, Y., Busman, T., Elmore, S. W., Rosenberg, S. H., Krivoshik, A. P., Enschede, S. H., & Humerickhouse, R. A.
- Affiliations
- National Institutes of Health (US)
- Roswell Park Comprehensive Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- University of Southern California (US)
- Abbott (United States) (US)
- Corresponding author
- Wilson, Wyndham H
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 11
- Issue
- 12
- Pages
- 1149-1159
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC3025495
- OpenAlex
- W2150680216
- Cited by
- 876
- References
- 47
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 66 · 2023: 49 · 2022: 66 · 2021: 69 · 2020: 70 · 2019: 43 · 2018: 42 · 2017: 53 · 2016: 52 · 2015: 63 · 2014: 60 · 2013: 55 · 2012: 50
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Abbott Fund
- Abbott Laboratories
- National Institutes of Health
- National Cancer Institute (ZIABC010716)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Keywords
- navitoclax, BCL-2 inhibitor, Bcl-xL, lymphoid malignancies, relapsed/refractory lymphoma, dose-limiting toxicity, thrombocytopenia, neutropenia, anemia, pharmacokinetics, pharmacodynamics, T cell proliferation, platelet function, antitumour activity, intermittent dosing
- MeSH terms
- Aged, Aniline Compounds, Antineoplastic Agents, Blood Platelets, Dosage Forms, Humans, Lymphoma, Middle Aged, Sulfonamides, T-Lymphocytes, Survival Analysis, Drug Delivery Systems, Proto-Oncogene Proteins c-bcl-2, Maximum Tolerated Dose
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
