© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 13, 1031-1032,
July 3, 2002
© 2002 Oxford University Press
CORRESPONDENCE |
Re: Blocking Oncogenic Ras Signaling for Cancer Therapy
Affiliations of authors: S. Canevari, M. Figini, Unit of Molecular Therapies, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy; S. Biocca, Department of Neuroscience, University of Rome "Tor Vergata," Italy.
Correspondence to: S. Canevari, Ph.D., Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy(e-mail: Canevari{at}istitutotumori.mi.it).
We congratulate Adjei (1) on his excellent, comprehensive, and timely review on Ras signaling and the therapeutic implications of blocking this signaling. Perhaps space constraints and a major focus on pharmacologic aspects prevented any discussion of a promising alternative approach to perturbing Ras membrane localization, namely, the diversion of intracellular trafficking by an intracellular antibody (Fig.1
).
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After the initial formal proof of intracellular antibody expression and targeting within the cell in 1990 [see specific publication cited in (2)], this approach was successfully applied to inhibit the function of several intracellular gene products, including p21Ras (2). The p21Ras molecule appears to be particularly sensitive to intracellular antibody-mediated perturbation of its precise localization to the inner face of the plasma membrane, which is crucial for its activity. Thus, anti-Ras intracellular antibodies with cytoplasmic targeting signals have been shown to divert p21Ras from its intracellular location and to address the antigen–antibody complex to the degradative compartment of the cell (3,4). Such intracellular antibodies are effective irrespective of the epitope recognized, the binding affinity, or the mutant status of the Ras protein broadening the spectrum of intracellular antibodies with potential therapeutic usefulness. In an animal model, intratumor injection of anti-Ras intracellular antibodies expressed by an adenoviral vector resulted in a statistically significant tumor regression, despite a low efficiency of in vivo transduction (5). The striking effects on tumors in that study implicate "bystander" mechanisms that amplify the direct inhibitory activity of the intracellular antibodies.
Anti-erbB-2 [see references cited in (6)] and p53 (7) intracellular antibodies targeted, respectively, to endoplasmic reticulum and to cytoplasm/nucleus have been validated in several preclinical in vitro models as selective and potent antitumor agents. Furthermore, adenoviral constructs expressing anti-erbB-2 intracellular antibody demonstrated in vivo antitumor activity leading to prolongation of survival in ovarian cancer animal models; these constructs were recently used in a phase I trial to determine the safety profile and gene transfer efficacy after intraperitoneal administration in ovarian cancer patients (6).
Rational approaches to engineering antibody regions suited for optimal expression in the desired intracellular compartment, together with improved vector design and strategies that engage bystander mechanisms, hold the promise of enhancing the feasibility and efficacy of intracellular antibody gene therapy.
In conclusion, the high level of specificity observed in preclinical studies and the very limited side effects reported in the first clinical application of intracellular antibody technology (6) suggest the value of increased efforts to fully explore the clinical utility of intracellular antibodies directed against p21Ras or other oncogenic molecules. These reagents might be used alone or in combination with other selective inhibitors of oncogene signaling such as farnesyl/geranylgeranyl transferase [see (1) for details] or tyrosine kinase inhibitors.
REFERENCES
1
Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001;93:1062–74.
2 Cattaneo A, Biocca S. Intracellular antibodies: development and applications. Berlin (Germany): Springer-Verlag; 1997. p. 1–196.
3 Lener M, Horn IR, Cardinale A, Messina S, Nielsen UB, Rybak SM, et al. Diverting a protein from its cellular location by intracellular antibodies: the case of p21 Ras. Eur J Biochem 2000;267:1196–205.[Medline]
4 Cardinale A, Filesi I, Biocca S. Aggresome formation by anti-Ras intracellular scFv fragments. The fate of the antigen-antibody complex. Eur J Biochem 2001;268:268–77.[Medline]
5
Cochet O, Kenigsberg M, Delumeau I, Virone-Oddos A, Multon MC, Fridman WH, et al. Intracellular expression of an antibody fragment-neutralizing p21 Ras promotes tumor regression. Cancer Res 1998;58:1170–6.
6
Alvarez RD, Barnes MN, Gomez-Navarro J, Wang M, Strong TV, Arafat W, et al. A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I trial. Clin Cancer Res 2000;6:3081–7.
7 Cohen PA, Mani JC, Lane DP. Characterization of a new intrabody directed against the N-terminal region of human p53. Oncogene 1998;17:2445–56.[CrossRef][Medline]
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