This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alley, M. C. Articles by Sausville, E. A. Search for Related Content PubMed PubMed Citation Articles by Alley, M. C. Articles by Sausville, E. A.

SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity

Part 2: Efficacy Evaluations

¹ Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda and Frederick, Maryland; ² Southern Research Institute, Birmingham, Alabama; ³ Cancer Research UK Drug-DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom; and ⁴ Cancer Research UK Gene Targeted Drug Design Research Group, School of Pharmacy, University of London, London, United Kingdom

Pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. In addition, SJG-136 is highly active in vivo in hollow fiber assays. In the current investigation, SJG-136 was evaluated for in vivo efficacy in 10 tumor models selected on the basis of sensitivity of cells grown in the hollow fiber and in vitro time course assays: LOX IMVI and UACC-62 (melanomas); OVCAR-3 and OVCAR-5 (ovarian carcinomas); MDA-MB-435 (breast carcinoma); SF-295 and C-6 (gliomas); LS-174T (colon carcinoma); HL-60 TB (promyelocytic leukemia); and NCI-H522 (lung carcinoma). SJG-136 was active against small (150 mg) and large (250–400 mg) xenografts with tumor mass reductions in all 10 models. In addition, significant growth delays occurred in nine models, cell kill in six models ranged between 1.9 and 7.2 logs, and there were 1 to 4/6 tumor-free responses in six models. SJG-136 is active following i.v. bolus injections, as well as by 5-day continuous infusions. Of all of the schedules tested, bolus administrations for 5 consecutive days (qdx5) conferred the greatest efficacy. SJG-136 is active over a wide dosage range in athymic mouse xenografts: on a qdx5 schedule, the maximum-tolerated dose was 120 µg/kg/dose (total dose: 0.6 mg/kg = 1.8 mg/m²) and the minimum effective dose in the most sensitive model (SF-295) was 16 µg/kg/dose (total dose: 0.08 mg/kg = 0.24 mg/m²). Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, which are planned to commence shortly.

This article has been cited by other articles:

				W. Li, S. Chou, A. Khullar, and B. Gerratana Cloning and Characterization of the Biosynthetic Gene Cluster for Tomaymycin, an SJG-136 Monomeric Analog Appl. Envir. Microbiol., May 1, 2009; 75(9): 2958 - 2963. [Abstract] [Full Text] [PDF]

				D. Hochhauser, T. Meyer, V. J. Spanswick, J. Wu, P. H. Clingen, P. Loadman, M. Cobb, L. Gumbrell, R. H. Begent, J. A. Hartley, et al. Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors Clin. Cancer Res., March 15, 2009; 15(6): 2140 - 2147. [Abstract] [Full Text] [PDF]

				G. P. Prevost, M. O. Lonchampt, S. Holbeck, S. Attoub, D. Zaharevitz, M. Alley, J. Wright, M. C. Brezak, H. Coulomb, A. Savola, et al. Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G{alpha}/G{beta}{gamma} Protein Complex. Cancer Res., September 15, 2006; 66(18): 9227 - 9234. [Abstract] [Full Text] [PDF]

				S. Arnould, V. J. Spanswick, J. S. Macpherson, J. A. Hartley, D. E. Thurston, D. I. Jodrell, and S. M. Guichard Time-dependent cytotoxicity induced by SJG-136 (NSC 694501): influence of the rate of interstrand cross-link formation on DNA damage signaling. Mol. Cancer Ther., June 1, 2006; 5(6): 1602 - 1609. [Abstract] [Full Text] [PDF]

				W. C. Zamboni, L. L. Jung, M. J. Egorin, D. R. Hamburger, E. Joseph, R. Jin, S. Strychor, R. K. Ramanathan, and J. L. Eiseman Relationship between Plasma Exposure of 9-Nitrocamptothecin and Its 9-Aminocamptothecin Metabolite and Antitumor Response in Mice Bearing Human Colon Carcinoma Xenografts Clin. Cancer Res., July 1, 2005; 11(13): 4867 - 4874. [Abstract] [Full Text] [PDF]

				P. H. Clingen, I. U. De Silva, P. J. McHugh, F. J Ghadessy, M. J. Tilby, D. E. Thurston, and J. A. Hartley The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 Nucleic Acids Res., June 8, 2005; 33(10): 3283 - 3291. [Abstract] [Full Text] [PDF]

				J. A. Hartley, V. J. Spanswick, N. Brooks, P. H. Clingen, P. J. McHugh, D. Hochhauser, R. B. Pedley, L. R. Kelland, M. C. Alley, R. Schultz, et al. SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity: Part 1: Cellular Pharmacology, In vitro and Initial In vivo Antitumor Activity Cancer Res., September 15, 2004; 64(18): 6693 - 6699. [Abstract] [Full Text] [PDF]