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Related Concept Videos

Preclinical Development: Overview01:28

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...

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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Initial testing of dasatinib by the pediatric preclinical testing program.

E Anders Kolb1, Richard Gorlick, Peter J Houghton

  • 1The Children's Hospital at Montefiore, Bronx, New York, USA. eakolb@nemours.org

Pediatric Blood & Cancer
|October 5, 2007
PubMed
Summary

Dasatinib shows activity against specific cancer cell lines and a Philadelphia chromosome-positive acute lymphoblastic leukemia xenograft. This dual tyrosine kinase inhibitor demonstrated limited in vivo efficacy in solid tumors but significant anti-leukemia effects.

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Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Dasatinib is a dual inhibitor of src and abl tyrosine kinases.
  • It is FDA-approved for imatinib mesylate-resistant chronic myeloid leukemia.

Purpose of the Study:

  • To evaluate the preclinical efficacy of dasatinib against a panel of pediatric solid tumors and leukemia xenografts.
  • To determine dasatinib's activity in vitro and in vivo.

Main Methods:

  • Dasatinib was tested in vitro against 22 cell lines from the Pediatric Preclinical Testing Program (PPTP) panel.
  • In vivo testing involved oral administration of dasatinib (50 mg/kg) to xenograft models.

Main Results:

  • Dasatinib exhibited selective in vitro activity, with IC(50) values around 10 nM for AML line Kasumi-1 and rhabdoid tumor line CHLA-266.
  • In vivo, dasatinib showed limited activity against solid tumor xenografts but significant efficacy against a Philadelphia chromosome-positive ALL xenograft, with complete response observed.

Conclusions:

  • Dasatinib demonstrates potent in vitro activity against a subset of cancer cell lines.
  • The drug shows promising in vivo activity against specific leukemia xenografts, particularly Ph(+) ALL, warranting further investigation.