Biological Basis of Radiation Sensitivity

The two research groups from Long Island Jewish Medical Center and Yale University have collaborated to write an excellent overview of the biological basis of radio-sensitivity, especially as it applies to radiotherapy. The content of the paper reflects the excellence of these investigators’ contributions to the field of radiobiology. It is particularly refreshing to read an account of radiobiology that does not resort to the mathematical overanalysis that has plagued the field in the past.

Ionizing Radiation, Cytokines, and Growth Factors

Ten years ago, our group, in collaboration with the Kufe laboratory at Harvard, reported the transcriptional and post-transcriptional induction of the gene encoding the multifunctional cytokine tumor necrosis factor–alpha (TNF-alpha) by ionizing radiation.[1,2] We proposed that radiation-inducible cytokines and growth factors might have autocrine and paracrine effects on tumor and normal cells. Therefore, we suggested that the effects observed following exposure of tumors and normal tissues to ionizing radiation might be due not only to the direct effects of x-rays on DNA but also to the effects of cytokines and growth factors.

Rosen and colleagues present a very interesting analysis of work that has been done since these original observations. One of the most important discoveries is that ionizing radiation induces transforming growth factor–beta (TGF-beta). This observation suggests that hepatic, pulmonary, and skin fibrosis is due to secretion of this cytokine. One implication of these findings is that blocking the induction of TGF-beta may ameliorate some of the long-term, deleterious effects of radiotherapy.[3-5]

In another seminal observation, the Fuks laboratory noted that ionizing radiation induces basic fibroblast growth factor (bFGF) in endothelial cells. This observation has potential clinical implications, in that it suggests a strategy for radioprotection of some normal tissues.[6,7]

Molecular Pathways of Radiation Response

Rosen et al do a solid job of outlining the molecular pathways of the radiation response in mammalian cells. They describe genes and proteins that govern apoptosis, cell-cycle distribution, and DNA repair following the administration of radiation therapy.

An interesting concept to apply to radiotherapy is molecular footprinting of the radiation response by DNA arrays.[8] Using DNA “chip” technology, it is possible to develop profiles of gene expression in various tumors and normal tissues and to potentially exploit differences in these gene profiles in radiotherapy. For example, as new molecular targets are identified, small peptide inhibitors of genes involved in checkpoint control or DNA repair might be developed to enhance the cytotoxicity of radiation in tumor cells.

Tumor Angiogenesis and Radiation Oncology

Recent advances in the field of tumor angiogenesis have important implications for radiation oncology. Tumor blood vessels are derived principally from host blood vessels, are genetically stable, and, therefore, are unlikely to evolve resistance to cytotoxic agents. Also, it has been proposed that one tumor vessel supplies up to 10² to10⁵ tumor cells.

Conventional radiation therapy probably does not target the tumor vasculature. Employing a variety of early-stage angiogenesis inhibitors in combination with cytotoxic agents, Teicher and colleagues enhanced tumor regression in experimental systems.[9]

In 1998, Mauceri et al demonstrated that the naturally occurring angiogenesis inhibitor, angiostatin, enhances the antitumor effects of therapeutic radiation without producing a concomitant increase in acute normal tissue damage.[10] In a subsequent paper, Gorski et al reported that employing neutralizing antibodies to vascular endothelial growth factor (VEGF) combined with radiation enhanced the antitumor effects of both treatments.[11] Considered together, these reports suggest that adding an angiogenesis inhibitor or blocking a promoter of angiogenesis might enhance the therapeutic effects of radiotherapy without amplifying its effects on normal tissue.

Summary

Molecular biology is expanding the potential therapeutic range of radiation oncology. New advances in the field of tumor immunology, radiation chemistry, and imaging may further expand radiotherapeutic options.

References:

1. Hallahan DE, Spriggs DR, Beckett MA, et al: Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci USA 86:10104-10107, 1989.

2. Sherman ML, Datta R, Hallahan DE, et al: Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes. J Clin Invest 87:1794-1797, 1991.

3. Santin AD, Hiserodt JC, DiSaia PJ, et al: Differential effects of high-dose gamma irradiation on the production of transforming growth factor-beta in fresh and established human ovarian cancer. Gynecol Oncol 61(3):403-408, 1996.

4. Martin M, Vozenin MC, Gault N, et al: Coactivation of Pl activity and TGF-betal gene expression in the stress response of normal skin cells to ionizing radiation. Oncogene 15(8):981-989, 1997.

5. Ehrhart EJ, Segarini P, Tsang ML, et al: Latent transforming growth factor beta 1 activation in situ: Quantitative and functional evidence after low-dose gamma-irradiation. FASEB J 11(12):991-1002, 1997.

6. Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A, et al: Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells. Cancer Res 51(l0):2552-2558, 1991.

7. Fuks Z, Persand RS, Alfieri S, et al: Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res 54(10):2582-2590, 1994.

8. Galperin MY: Bioinformatics for all! ABRF meeting: Bioinformatics and biomolecular technologies: Linking genomes, proteomes and biochemistry, Durham, North Carolina, USA, 19-22 March 1999: Association of biomolecular resource facilities. Trends Genet 15(7):257-258, 1999.

9. Teicher BA, Sotomayor EA, Huang ZD: Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 52(23):6702-6704, 1992.

10. Mauceri HJ, Hanna NN, Beckett MA, et al: Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394(6690):287-291, 1998.

11. Gorski DH, Beckett MA, Jaskowiak NT, et al: Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 59(14):3374-3378, 1999.