Selective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma.

نویسندگان

  • Samuel Y Ng
  • Matthew S Davids
چکیده

ABT-199, a second-generation BH3 mimetic, is an orally bioavailable, small molecule inhibitor that selectively targets B-cell lymphoma/leukemia 2 (Bcl-2). Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. First-generation BH3 mimetics such as navitoclax (ABT-263) had a broad range of inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, and Bcl-w. This drug demonstrated antitumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL); however, on-target Bcl-XL inhibition led to dose-dependent thrombocytopenia and posed a barrier to maximizing the activity of this agent. Through an elegant reengineering of navitoclax, ABT-199 was developed as a Bcl-2-selective small molecule inhibitor. In preclinical studies, ABT-199 was shown to have greater than 100-fold selectivity for Bcl-2 over Bcl-XL. This selectivity has been consistent with the early results of the ongoing phase 1 clinical trial of ABT-199 in which the drug has demonstrated high rates of activity in relapsed/refractory CLL and NHL without dose-dependent thrombocytopenia. On-target tumor lysis syndrome (TLS) has been observed in a subset of patients treated with ABT-199, but changes in initial dosing and stepwise dose escalation have now been implemented to mitigate this risk. Ongoing correlative studies are being performed to help identify patients with the highest chance of response and the greatest risk for TLS.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Significance of Bcl-2 and Bcl-6 immunostaining in B-Non Hodgkin's lymphoma

The determination of prognosis for B-Non-Hodgkin's lymphoma (NHL) is known to be related to the multiple differences in tumor cell biology. Bcl-2 and Bcl-6 are two markers linked to germinal center B cells. Both markers are thought to have an effect on prognosis of mature B-cell neoplasms. Forty-four patients with chronic B-cell neoplasm were included; Bcl-2 and Bcl-6 expression by immunohistoc...

متن کامل

Genetic Variations of Tumor Necrosis Factor –α-308 and Lymphtoxin-α+252 in Non-Hodgkin Lymphoma and Acute Lymphoblastic Leukemia Patients

  Objective(s): Non- Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) are two main hematological malignances which have been driven from lymphoid tissue. Genetic polymorphisms in tumor necrosis factor-α (TNF-α) -308 and lymphotoxin-α (LT-α) +252 may affect their transcription and expression which leads to their high plasma level. The frequency of the TNF-α (-308) and LT-...

متن کامل

Expression of bcl-3 in chronic lymphocytic leukemia correlates with trisomy 12 and abnormalities of chromosome 19.

The bcl-3 gene at chromosome 19q13 encodes a member of the IkB family involved in regulating the nuclear factor kB pathway. Originally identified by its involvement in the t(14:19)(q32;q13), bcl-3 expression recently has been reported in 12% of non-Hodgkin lymphomas and 41% of Hodgkin lymphomas. Because the t(14;19) is detected most commonly in chronic lymphocytic leukemia (CLL), we assessed fo...

متن کامل

Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms.

The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas ...

متن کامل

A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Clinical advances in hematology & oncology : H&O

دوره 12 4  شماره 

صفحات  -

تاریخ انتشار 2014