pIXY321 protects against Ara-C or taxol-induced apoptosis and loss of clonogenic survival of normal human bone marrow progenitor cells

K. Bhalla, A. M. Ibrado, J. E. Brandt, S. Ray, Y. Huang, C. Tang, A. Nawabi, R. Hoffman

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

By suppressing apoptosis, hemopoietic growth factors (HGFs) promote the survival of CD34+, HLA-DR+ marrow cells that are enriched for hemopoietic progenitor cells (HPC). In the present studies, we have examined the effects of pIXY321, a genetically engineered fusion protein of GM-CSF and IL-3 (GM-CSF/IL-3), on high-dose Ara-C (HIDAC) and taxol-induced apoptosis and survival of a multilineage HPC, the CFU-GEMM. Exposure to 1.0 μmol/l taxol for 24 h or HIDAC ≥ 10 μmol/l for 4 h induced internucleosomal DNA fragmentation and the morphologic features of apoptosis in CD34+, HLA-DR+ cells. These treatments were associated with ≥ 50% inhibition of the assayable CFU-GEMM colony numbers. Incubation in serum-free medium (SFM) alone for 24 h also induced apoptosis of CD34+, HLA-DR+ cells, which was associated with reduced intracellular levels of the bcl-2 gene product p26BCL-2. Co-treatment with pIXY321 (10 ng/ml) inhibited apoptosis of CD34+, HLA-DR+ cells incubated in SFM, without significantly increasing the intracellular p26BCL-2 levels. Furthermore, co-treatment with pIXY321 significantly reduced taxol- and Ara-C-induced apoptosis and promoted the survival of CFU-GEMM (P < 0.05). Taxol and Ara-C-mediated apoptosis of CD34+, HLA-DR+ cells, and its inhibition by pIXY321, was not accompanied by any significant alteration in the intracellular p26BCL-2 levels. By demonstrating that co-treatment with pIXY321 confers significant protection against apoptosis of CD34+, HLA-DR+ cells as well as promotes survival of normal HPC exposed to clinically relevant schedules and concentrations of taxol or Ara-C, these results support the design of chemotherapy regimens incorporating pIXY321 plus taxol and/or high-dose Ara-C for solid tumors and/or acute leukemias. It is hoped that the use of such a cytokine might maintain normal HPC numbers following chemotherapy, therefore avoiding prolonged suppression.

Original languageEnglish (US)
Pages (from-to)1851-1856
Number of pages6
JournalLeukemia
Volume9
Issue number11
StatePublished - Nov 1995

Keywords

  • Apoptosis
  • Ara-C
  • Normal CD34 bone marrow progenitor cells
  • pIXY321
  • Taxol

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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