Predicting Effectiveness of Imatinib Mesylate in Tumors Expressing Platelet-Derived Growth Factors (PDGF-AA, PDGF-BB), Stem Cell Factor Ligands and Their Respective Receptors (PDGFR-α, PDGFR-β, and c-kit).

INTRODUCTION

This research aims to optimize and predict the effectiveness of imatinib mesylate (imatinib) in tumors expressing platelet-derived growth factors (PDGF-AA, BB), kit/stem cell factor (SCF) ligands and their respective receptors (PDGFR-α, PDGFR-β, and c-kit).

MATERIAL AND METHODS

Samples of normal primary human T cells were incubated with graded concentrations of 1-5 μM imatinib. The energy yield by imatinib doses in those samples was identified in H-thymidine proliferation assay as described before in earlier studies. Tumor models of human pancreatic adenocarcinoma L3.6pl (PDGFAA/PDGFR-α-positive and KIT-negative), human male gonad Leydig tumor cells MA10 (PDGF-AA/PDGFR-α- positive and KIT-positive), human small-cell lung cancer [H209 (KIT-positive), NCI-H526 (PDGFR β-positive and KIT-positive), and NCI-H82 (PDGFR β-positive and KIT-negative)], and human neuroblastoma SMS-KCNR (PDGF-BB/PDGFR-β-positive and KIT-positive) in athymic nude mice were used. The antitumor activity of different doses of imatinib in different regimens in those xenografts was predicted as described before in earlier studies.

RESULTS

The energy yield by drug doses was perfectly logarithmic correlated (r = 1) with the drug dose. An efficient dose-energy model with perfect fit (R = 1) estimating the energy yield by imatinib doses has been established to administer the personalized dose. Predictions for the antitumor activity of imatinib in those xenografts using the dose-energy model and the histologic grade of the control animals were 100 % identical to those actually induced.

CONCLUSION

The effect of imatinib is transient and reversible, reduces tyrosine phosphorylation of tumor-derived PDGFR-α, PDGFR-β, and c-kit without affecting their levels of expression. A resumption of tumor growth nearly identical to the growth prior to therapy should be expected whenever the treatment is stopped. Tumors of PDGF-AA/PDGFR-α exhibit significant resistance to imatinib which requires administering imatinib three times a day, whereas resistance of tumors of PDGF-BB/PDGFR-β or KIT-positive is relatively lower which requires administering imatinib two times a day only to produce an actual inhibition 100 % identical to that predicted for tumor growth.