Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class.

Glioblastoma multiforme is the most common primary human brain tumor, and it is, for all practical purposes, incurable in adult patients. The high mortality rates reflect the fact that glioblastomas are resistant to adjuvant therapies (radiation and chemicals), the mode of action of which is cytotoxic. We show here that an p.o.-active small molecule kinase inhibitor of the 2-phenylaminopyrimidine class may have therapeutic potential for glioblastomas. STI571 inhibits the growth of U343 and U87 human glioblastoma cells that have been injected into the brains of nude mice, but it does not inhibit intracranial growth of ras-transformed cells. Studies on a broad panel of genetically validated human and animal cell lines show that STI571 acts by disruption of the ligand:receptor autocrine loops for platelet-derived growth factor that are a pervasive feature of malignant astrocytoma. The cellular response of glioblastoma cells to STI571 does not appear to involve an apoptotic mechanism.

[1]  Reuven Agami,et al.  Interaction of c-Abl and p73α and their collaboration to induce apoptosis , 1999, Nature.

[2]  Jijie Gu,et al.  p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage , 1999, Nature.

[3]  Antonio Costanzo,et al.  The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage , 1999, Nature.

[4]  M. Nistér,et al.  Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. , 1998, Cancer research.

[5]  P. Black,et al.  Detection of activated platelet-derived growth factor receptors in human meningioma. , 1997, Cancer research.

[6]  J. Bruner,et al.  Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas. , 1996, Neurosurgery.

[7]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[8]  O. Potapova,et al.  Platelet-derived growth factor-B/v-sis confers a tumorigenic and metastatic phenotype to human T98G glioblastoma cells. , 1996, Cancer research.

[9]  D. Louis,et al.  A tiger behind many doors: multiple genetic pathways to malignant glioma. , 1995, Trends in genetics : TIG.

[10]  A. Guha,et al.  Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop , 1995, International journal of cancer.

[11]  A. Ullrich,et al.  Inhibition of glioma cell growth by a truncated platelet-derived growth factor-beta receptor. , 1994, The Journal of biological chemistry.

[12]  C. Heldin,et al.  Activated platelet‐derived growth factor autocrine pathway drives the transformed phenotype of a human glioblastoma cell line , 1994, Journal of cellular physiology.

[13]  S. Shamah,et al.  Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells , 1993, Molecular and cellular biology.

[14]  C. Heldin,et al.  Reversion of autocrine transformation by a dominant negative platelet-derived growth factor mutant , 1993, Molecular and cellular biology.

[15]  C. Heldin,et al.  Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. , 1992, Cancer research.

[16]  A. van Koppen,et al.  Is PDGF really important? Testing the hypotheses. , 1991, Trends in genetics : TIG.

[17]  C. Heldin,et al.  Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. , 1991, The Journal of biological chemistry.

[18]  P. Black,et al.  Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. , 1990, The Journal of clinical investigation.

[19]  D Riddoch,et al.  Neoplasms of the central nervous system. , 1977, The Practitioner.

[20]  D. Louis,et al.  Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomas. , 1996, Cancer research.

[21]  D. Louis,et al.  CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. , 1996, Cancer research.

[22]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.

[23]  C. Heldin,et al.  Structure of platelet-derived growth factor: implications for functional properties. , 1993, Growth factors.