| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Cell Biology Section, Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892
The benzoquinonoid ansamycin antibiotics herbimycin A and geldanamycin have been shown to reverse the oncogenic phenotype of pp60vsrc transformed cells as well as induce differentiation in a number of in vitro model systems, reportedly due to their inhibition of src family protein tyrosine kinases. We now report that these agents are potent cytotoxins in vitro against a panel of highly malignant human tumor cell lines possessing primitive neural features. Proliferation and/or survival of fibroblasts, primary neuronal cultures, and several leukemia cell lines are unaffected at concentrations resulting in >99% cell loss in sensitive lines. The tumorigenicity in nude mice of sensitive cell lines can also be markedly reduced by either systemic or topical administration of these agents without apparent toxicity to the whole animal. The cytocidal action of these ansamycins is initiated very rapidly, is irreversible, and is clearly distinct from the delayed inhibition of src family kinases that has been reported previously. Due to their potency, relative selectivity, and novel mechanism(s) of action, these drugs could prove clinically useful in the therapy of a number of human cancers of neural derivation.
1 To whom requests for reprints should be addressed, at Pediatric Branch, National Cancer Institute, Building 10, Room 13N240, Bethesda, MD 20892.
Received 10/ 8/91. Accepted 1/23/92.
This article has been cited by other articles:
|
|
 |
|
  A. K. McCollum, K. B. Lukasiewicz, C. J. TenEyck, W. L. Lingle, D. O. Toft, and C. Erlichman Cisplatin abrogates the geldanamycin-induced heat shock response Mol. Cancer Ther., October 1, 2008; 7(10): 3256 - 3264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. McCollum, C. J. TenEyck, B. Stensgard, B. W. Morlan, K. V. Ballman, R. B. Jenkins, D. O. Toft, and C. Erlichman P-Glycoprotein-Mediated Resistance to Hsp90-Directed Therapy Is Eclipsed by the Heat Shock Response Cancer Res., September 15, 2008; 68(18): 7419 - 7427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Hecht Natural Products that Bind to Heat Shock Protein 90 Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Bagatell, L. Gore, M. J. Egorin, R. Ho, G. Heller, N. Boucher, E. G. Zuhowski, J. A. Whitlock, S. P. Hunger, A. Narendran, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of 17-N-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study Clin. Cancer Res., March 15, 2007; 13(6): 1783 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Sharp, K. Boxall, M. Rowlands, C. Prodromou, S. M. Roe, A. Maloney, M. Powers, P. A. Clarke, G. Box, S. Sanderson, et al. In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors Cancer Res., March 1, 2007; 67(5): 2206 - 2216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. McCollum, C. J. TenEyck, B. M. Sauer, D. O. Toft, and C. Erlichman Up-regulation of Heat Shock Protein 27 Induces Resistance to 17-Allylamino-Demethoxygeldanamycin through a Glutathione-Mediated Mechanism. Cancer Res., November 15, 2006; 66(22): 10967 - 10975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Carbone, J. A. Doorn, Z. Kiebler, B. R. Ickes, and D. R. Petersen Modification of Heat Shock Protein 90 by 4-Hydroxynonenal in a Rat Model of Chronic Alcoholic Liver Disease J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 8 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fumo, C. Akin, D. D. Metcalfe, and L. Neckers 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells Blood, February 1, 2004; 103(3): 1078 - 1084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Bisht, C. M. Bradbury, D. Mattson, A. Kaushal, A. Sowers, S. Markovina, K. L. Ortiz, L. K. Sieck, J. S. Isaacs, M. W. Brechbiel, et al. Geldanamycin and 17-Allylamino-17-demethoxygeldanamycin Potentiate the in Vitro and in Vivo Radiation Response of Cervical Tumor Cells via the Heat Shock Protein 90-Mediated Intracellular Signaling and Cytotoxicity Cancer Res., December 15, 2003; 63(24): 8984 - 8995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Goetz, D. O. Toft, M. M. Ames, and C. Erlichman The Hsp90 chaperone complex as a novel target for cancer therapy Ann. Onc., August 1, 2003; 14(8): 1169 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Tikhomirov and G. Carpenter Identification of ErbB-2 Kinase Domain Motifs Required for Geldanamycin-induced Degradation Cancer Res., January 1, 2003; 63(1): 39 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Isaacs, Y.-J. Jung, E. G. Mimnaugh, A. Martinez, F. Cuttitta, and L. M. Neckers Hsp90 Regulates a von Hippel Lindau-independent Hypoxia-inducible Factor-1alpha -degradative Pathway J. Biol. Chem., August 9, 2002; 277(33): 29936 - 29944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Sullivan and J. M. Pipas T Antigens of Simian Virus 40: Molecular Chaperones for Viral Replication and Tumorigenesis Microbiol. Mol. Biol. Rev., June 1, 2002; 66(2): 179 - 202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bonvini, T. Gastaldi, B. Falini, and A. Rosolen Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK), a Novel Hsp90-Client Tyrosine Kinase: Down-Regulation of NPM-ALK Expression and Tyrosine Phosphorylation in ALK+ CD30+ Lymphoma Cells by the Hsp90 Antagonist 17-Allylamino,17-demethoxygeldanamycin Cancer Res., March 1, 2002; 62(5): 1559 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Sausville Combining Cytotoxics and 17-Allylamino, 17-Demethoxygeldanamycin: Sequence and Tumor Biology Matters : Commentary re: P. Munster et al., Modulation of Hsp90 Function by Ansamycins Sensitizes Breast Cancer Cells to Chemotherapy-induced Apoptosis in an RB- and Schedule-dependent Manner. Clin. Cancer Res., 7: 2228-2236, 2001. Clin. Cancer Res., August 1, 2001; 7(8): 2155 - 2158. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jolly and R. I. Morimoto Role of the Heat Shock Response and Molecular Chaperones in Oncogenesis and Cell Death J Natl Cancer Inst, October 4, 2000; 92(19): 1564 - 1572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bagatell, G. D. Paine-Murrieta, C. W. Taylor, E. J. Pulcini, S. Akinaga, I. J. Benjamin, and L. Whitesell Induction of a Heat Shock Factor 1-dependent Stress Response Alters the Cytotoxic Activity of Hsp90-binding Agents Clin. Cancer Res., August 1, 2000; 6(8): 3312 - 3318. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. Stepanova, M. Finegold, F. DeMayo, E. V. Schmidt, and J. W. Harper The Oncoprotein Kinase Chaperone CDC37 Functions as an Oncogene in Mice and Collaborates with Both c-myc and Cyclin D1 in Transformation of Multiple Tissues Mol. Cell. Biol., June 15, 2000; 20(12): 4462 - 4473. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. D. Yorgin, S. D. Hartson, A. M. Fellah, B. T. Scroggins, W. Huang, E. Katsanis, J. M. Couchman, R. L. Matts, and L. Whitesell Effects of Geldanamycin, a Heat-Shock Protein 90-Binding Agent, on T Cell Function and T Cell Nonreceptor Protein Tyrosine Kinases J. Immunol., March 15, 2000; 164(6): 2915 - 2923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Vasilevskaya and P. J. O'Dwyer Effects of Geldanamycin on Signaling through Activator-Protein 1 in Hypoxic HT29 Human Colon Adenocarcinoma Cells Cancer Res., August 1, 1999; 59(16): 3935 - 3940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Grammatikakis, J.-H. Lin, A. Grammatikakis, P. N. Tsichlis, and B. H. Cochran p50cdc37 Acting in Concert with Hsp90 Is Required for Raf-1 Function Mol. Cell. Biol., March 1, 1999; 19(3): 1661 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. B. Pratt and D. O. Toft Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones Endocr. Rev., June 1, 1997; 18(3): 306 - 360. [Abstract] [Full Text]
|
|
|
|
|
|
L. F. Stancato, A. M. Silverstein, J. K. Owens-Grillo, Y.-H. Chow, R. Jove, and W. B. Pratt The hsp90-binding Antibiotic Geldanamycin Decreases Raf Levels and Epidermal Growth Factor Signaling without Disrupting Formation of Signaling Complexes or Reducing the Specific Enzymatic Activity of Raf Kinase J. Biol. Chem., February 14, 1997; 272(7): 4013 - 4020. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Schulte, M. V. Blagosklonny, C. Ingui, and L. Neckers Disruption of the Raf-1-Hsp90 Molecular Complex Results in Destabilization of Raf-1 and Loss of Raf-1-Ras Association J. Biol. Chem., October 13, 1995; 270(41): 24585 - 24588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Tikhomirov and G. Carpenter Geldanamycin Induces ErbB-2 Degradation by Proteolytic Fragmentation J. Biol. Chem., August 18, 2000; 275(34): 26625 - 26631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Fuller and A. W. Cuthbert Post-translational Disruption of the Delta F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Molecular Chaperone Complex with Geldanamycin Stabilizes Delta F508 CFTR in the Rabbit Reticulocyte Lysate J. Biol. Chem., November 22, 2000; 275(48): 37462 - 37468. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
