Chemoradiotherapy-resistant leukemias often express resistance genes which reduce clinical results from available cytotoxic agents. Clinical modulation of resistance gene products has been hampered by limited efficacy and normal tissue toxicities. Targeted polypeptide toxins which bind to defined receptors on neoplastic blasts and catalytically inactivate protein synthesis may provide a more specific and effective method of altering the apoptotic threshold of cells to cytotoxic drugs and radiation. The applicants have genetically engineered two ricin fusion proteins--GM-CSF-triple-site mutant RTB-RTA and GCSF-triple-site mutant RTB-RTA and tested a diphtheria toxin fusion protein--DTGMCSF and have demonstrated selective cytotoxicity to leukemic blasts for the GMCSF fusion toxins. The applicants propose to investigate the in vitro and in vivo efficacy of these reagents on altering the apoptopic threshold of drug resistant cells and to explore the molecular mechanism for synergy both in cell lines and fresh malignant cells.
Specific Aim 1 tests the ability of fusion toxins to alter the sensitivity of resistant cells to cytotoxic drugs.
Specific Aim 2 evaluates the molecular mechanism for synergy by measuring the intracellular concentrations of resistance gene products and the intracellular distribution of toxin in treated cells.
Specific Aim 3 measures the anti-tumor efficacy of ricin fusion proteins combined with cytotoxic drugs on resistant myeloid leukemias in SCID mice. The results should provide basic scientific information needed to describe the potential of fusion toxins to act as specific drug resistance modulators in therapy of refractory myeloid leukemias.
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