Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models
Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models. Experimental Design: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent a...
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| Published in | Clinical cancer research Vol. 14; no. 11; pp. 3268 - 3277 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Philadelphia, PA
American Association for Cancer Research
01.06.2008
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small
cell lung cancer (SCLC) xenograft models.
Experimental Design: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined
on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison
to standard cytotoxic agents, and induction of apoptosis.
Results: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions
of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor
regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several
clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy
and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic
schedules and was associated with significant induction of apoptosis.
Conclusions: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The
efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent. |
|---|---|
| AbstractList | Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small
cell lung cancer (SCLC) xenograft models.
Experimental Design: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined
on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison
to standard cytotoxic agents, and induction of apoptosis.
Results: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions
of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor
regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several
clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy
and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic
schedules and was associated with significant induction of apoptosis.
Conclusions: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The
efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent. Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models. Experimental Design: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis. Results: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis. Conclusions: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent. The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models. A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis. ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis. ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent. PURPOSEThe purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.EXPERIMENTAL DESIGNA panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis.RESULTSABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis.CONCLUSIONSABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent. |
| Author | Steven K. Tahir Marion Refici Xiufen Yang Michael J. Mitten Jessica Adickes Saul H. Rosenberg Joy Bauch Steven W. Elmore Debra Ferguson David J. Frost Alex R. Shoemaker Scott Ackler Anatol Oleksijew Christin Tse Kennan Marsh Baole Wang Jacqueline M. O'Connor Stephen W. Fesik |
| Author_xml | – sequence: 1 givenname: Alex R surname: SHOEMAKER fullname: SHOEMAKER, Alex R organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 2 givenname: Michael J surname: MITTEN fullname: MITTEN, Michael J organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 3 givenname: Joy surname: BAUCH fullname: BAUCH, Joy organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 4 givenname: Kennan surname: MARSH fullname: MARSH, Kennan organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 5 givenname: Steven K surname: TAHIR fullname: TAHIR, Steven K organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 6 surname: XIUFENYANG fullname: XIUFENYANG organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 7 givenname: Christin surname: TSE fullname: TSE, Christin organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 8 givenname: Stephen W surname: FESIK fullname: FESIK, Stephen W organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 9 givenname: Saul H surname: ROSENBERG fullname: ROSENBERG, Saul H organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 10 givenname: Steven W surname: ELMORE fullname: ELMORE, Steven W organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 11 givenname: Jessica surname: ADICKES fullname: ADICKES, Jessica organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 12 givenname: Scott surname: ACKLER fullname: ACKLER, Scott organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 13 givenname: Marion surname: REFICI fullname: REFICI, Marion organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 14 givenname: Debra surname: FERGUSON fullname: FERGUSON, Debra organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 15 givenname: Anatol surname: OLEKSIJEW fullname: OLEKSIJEW, Anatol organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 16 givenname: Jacqueline M surname: O'CONNOR fullname: O'CONNOR, Jacqueline M organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 17 surname: BAOLE WANG fullname: BAOLE WANG organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States – sequence: 18 givenname: David J surname: FROST fullname: FROST, David J organization: Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois, United States |
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| Keywords | Lung disease Respiratory disease Animal Lung cancer Bonchopulmonary small cell carcinoma C-Onc gene Bronchus disease Inhibitor Malignant tumor Biological activity Protooncogene Cancer |
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| Snippet | Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small
cell lung cancer (SCLC)... The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft... Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC)... PURPOSEThe purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC)... |
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| SubjectTerms | ABT-263 Aniline Compounds - administration & dosage Animals Antineoplastic agents Antineoplastic Agents - administration & dosage apoptosis Bcl-2 Biological and medical sciences Carcinoma, Small Cell - drug therapy Dose-Response Relationship, Drug Humans Lung Neoplasms - drug therapy Medical sciences Mice Mice, Nude Pharmacology. Drug treatments Pneumology Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - drug effects small cell lung cancer Sulfonamides - administration & dosage Tumors of the respiratory system and mediastinum xenograft Xenograft Model Antitumor Assays |
| Title | Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models |
| URI | http://clincancerres.aacrjournals.org/content/14/11/3268.abstract https://www.ncbi.nlm.nih.gov/pubmed/18519752 https://search.proquest.com/docview/71623925 |
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