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The Unique Physiology of Solid Tumors: Opportunities (and Problems) for Cancer Therapy¹

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468

The physiology of solid tumors differs from that of normal tissues in a number of important aspects, the majority of which stem from differences between the two vasculatures. Compared with the regular, ordered vasculature of normal tissues, blood vessels in tumors are often highly abnormal, distended capillaries with leaky walls and sluggish flow. Tumor growth also requires continuous new vessel growth, or angiogenesis. These physiological differences can be problems for cancer treatment; for example, hypoxia in solid tumors leads to resistance to radiotherapy and to some anticancer drugs. However, these differences can also be exploited for selective cancer treatment. Here we review four such areas that are under active investigation: (a) hypoxia-selective cytotoxins take advantage of the unique low oxygen tension in the majority of human solid tumors. Tirapazamine, a drug in the final stages of clinical trials, is one of the more promising of these agents; (b) leaky tumor blood vessels can be exploited using liposomes that have been sterically stabilized to have a long intravascular half-life, allowing them to selectively accumulate in solid tumors; (c) the tumor microenvironment is a stimulus to angiogenesis, and inhibition of angiogenesis can be a powerful anticancer therapy not susceptible to acquired drug resistance; and (d) we discuss attempts to use gene therapy activated either by the low oxygen environment or by necrotic regions of tumors.

¹ Supported by USPHS Grants CA 15201, CA 67166 (to J. M. B.), and CA 64489 (to A. J. G.).

² To whom requests for reprints should be addressed, at Division of Radiation Biology (CBRL-GK103), Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305-5468. Phone: (650) 723-5881; Fax: (650) 723-7382.

Received 12/31/97. Revised 2/ 6/98. Accepted 2/17/98.

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				K. L. Blackwell, J. P. Kirkpatrick, S. A. Snyder, G. Broadwater, F. Farrell, L. Jolliffe, D. M. Brizel, and M. W. Dewhirst Human Recombinant Erythropoietin Significantly Improves Tumor Oxygenation Independent of Its Effects on Hemoglobin Cancer Res., October 1, 2003; 63(19): 6162 - 6165. [Abstract] [Full Text] [PDF]

				K. O. Hicks, F. B. Pruijn, J. R. Sturman, W. A. Denny, and W. R. Wilson Multicellular Resistance to Tirapazamine Is Due to Restricted Extravascular Transport: A Pharmacokinetic/Pharmacodynamic Study in HT29 Multicellular Layer Cultures Cancer Res., September 15, 2003; 63(18): 5970 - 5977. [Abstract] [Full Text] [PDF]

				R. A. Gatenby and T. L. Vincent Application of quantitative models from population biology and evolutionary game theory to tumor therapeutic strategies Mol. Cancer Ther., September 1, 2003; 2(9): 919 - 927. [Abstract] [Full Text] [PDF]

				Q.-T. Le and A. J. Giaccia HIF-{alpha}, a Gender Independent Transcription Factor Clin. Cancer Res., July 1, 2003; 9(7): 2391 - 2393. [Full Text] [PDF]

				G. Acs, P. J. Zhang, C. M. McGrath, P. Acs, J. McBroom, A. Mohyeldin, S. Liu, H. Lu, and A. Verma Hypoxia-Inducible Erythropoietin Signaling in Squamous Dysplasia and Squamous Cell Carcinoma of the Uterine Cervix and Its Potential Role in Cervical Carcinogenesis and Tumor Progression Am. J. Pathol., June 1, 2003; 162(6): 1789 - 1806. [Abstract] [Full Text] [PDF]

				R. K. Reddy, C. Mao, P. Baumeister, R. C. Austin, R. J. Kaufman, and A. S. Lee Endoplasmic Reticulum Chaperone Protein GRP78 Protects Cells from Apoptosis Induced by Topoisomerase Inhibitors: ROLE OF ATP BINDING SITE IN SUPPRESSION OF CASPASE-7 ACTIVATION J. Biol. Chem., May 30, 2003; 278(23): 20915 - 20924. [Abstract] [Full Text] [PDF]

				A. D. Colevas, J. M. Brown, S. Hahn, J. Mitchell, K. Camphausen, and C. N. Coleman Development of Investigational Radiation Modifiers J Natl Cancer Inst, May 7, 2003; 95(9): 646 - 651. [Full Text] [PDF]

				T. N. Seagroves, D. Hadsell, J. McManaman, C. Palmer, D. Liao, W. McNulty, B. Welm, K.-U. Wagner, M. Neville, and R. S. Johnson HIF1{alpha} is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland Development, April 15, 2003; 130(8): 1713 - 1724. [Abstract] [Full Text] [PDF]

				G. Micheletti, M. Poli, P. Borsotti, M. Martinelli, B. Imberti, G. Taraboletti, and R. Giavazzi Vascular-targeting Activity of ZD6126, a Novel Tubulin-binding Agent Cancer Res., April 1, 2003; 63(7): 1534 - 1537. [Abstract] [Full Text] [PDF]

				E. M. Hammond, M. J. Dorie, and A. J. Giaccia ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation J. Biol. Chem., March 28, 2003; 278(14): 12207 - 12213. [Abstract] [Full Text] [PDF]

				N. Denko, K. Wernke-Dollries, A. B. Johnson, E. Hammond, C.-M. Chiang, and M. C. Barton Hypoxia Actively Represses Transcription by Inducing Negative Cofactor 2 (Dr1/DrAP1) and Blocking Preinitiation Complex Assembly J. Biol. Chem., February 14, 2003; 278(8): 5744 - 5749. [Abstract] [Full Text] [PDF]

				S. S. Correa, G. N. Mauldin, G. E. Mauldin, and A. K. Patnaik Efficacy of Cobalt-60 Radiation Therapy for the Treatment of Nasal Cavity Nonkeratinizing Squamous Cell Carcinoma in the Dog J. Am. Anim. Hosp. Assoc., January 1, 2003; 39(1): 86 - 89. [Abstract] [Full Text] [PDF]

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				Q.-T. Le, P. D. Sutphin, S. Raychaudhuri, S. C. T. Yu, D. J. Terris, H. S. Lin, B. Lum, H. A Pinto, A. C. Koong, and A. J. Giaccia Identification of Osteopontin as a Prognostic Plasma Marker for Head and Neck Squamous Cell Carcinomas Clin. Cancer Res., January 1, 2003; 9(1): 59 - 67. [Abstract] [Full Text] [PDF]

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				P. C. Gokhale, C. Zhang, J. T. Newsome, J. Pei, I. Ahmad, A. Rahman, A. Dritschilo, and U. N. Kasid Pharmacokinetics, Toxicity, and Efficacy of Ends-modified raf Antisense Oligodeoxyribonucleotide Encapsulated in a Novel Cationic Liposome Clin. Cancer Res., November 1, 2002; 8(11): 3611 - 3621. [Abstract] [Full Text] [PDF]

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				Y. Ogiso, A. Tomida, and T. Tsuruo Nuclear Localization of Proteasomes Participates in Stress-inducible Resistance of Solid Tumor Cells to Topoisomerase II-directed Drugs Cancer Res., September 1, 2002; 62(17): 5008 - 5012. [Abstract] [Full Text] [PDF]

				K. M. Comerford, T. J. Wallace, J. Karhausen, N. A. Louis, M. C. Montalto, and S. P. Colgan Hypoxia-inducible Factor-1-dependent Regulation of the Multidrug Resistance (MDR1) Gene Cancer Res., June 1, 2002; 62(12): 3387 - 3394. [Abstract] [Full Text] [PDF]

				G. Hopfl, R. H. Wenger, U. Ziegler, T. Stallmach, O. Gardelle, R. Achermann, M. Wergin, B. Kaser-Hotz, H. M. Saunders, K. J. Williams, et al. Rescue of Hypoxia-inducible Factor-1{alpha}-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor Cancer Res., May 1, 2002; 62(10): 2962 - 2970. [Abstract] [Full Text] [PDF]

				E. M. Hammond, N. C. Denko, M. J. Dorie, R. T. Abraham, and A. J. Giaccia Hypoxia Links ATR and p53 through Replication Arrest Mol. Cell. Biol., March 15, 2002; 22(6): 1834 - 1843. [Abstract] [Full Text] [PDF]

				C. N. Coleman, J. B. Mitchell, and K. Camphausen Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm? J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615. [Full Text] [PDF]

				A. Fyles, M. Milosevic, D. Hedley, M. Pintilie, W. Levin, L. Manchul, and R. P. Hill Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix Cancer J. Clin. Oncol., February 1, 2002; 20(3): 680 - 687. [Abstract] [Full Text] [PDF]

				J. R. Griffiths, P. M. J. McSheehy, S. P. Robinson, H. Troy, Y.-L. Chung, R. D. Leek, K. J. Williams, I. J. Stratford, A. L. Harris, and M. Stubbs Metabolic Changes Detected by in Vivo Magnetic Resonance Studies of HEPA-1 Wild-Type Tumors and Tumors Deficient in Hypoxia-inducible Factor-1{beta} (HIF-1{beta}): Evidence of an Anabolic Role for the HIF-1 Pathway Cancer Res., February 1, 2002; 62(3): 688 - 695. [Abstract] [Full Text] [PDF]

				E. Auzenne, N. J. Donato, C. Li, E. Leroux, R. E. Price, D. Farquhar, and J. Klostergaard Superior Therapeutic Profile of Poly-L-Glutamic Acid-Paclitaxel Copolymer Compared with Taxol in Xenogeneic Compartmental Models of Human Ovarian Carcinoma Clin. Cancer Res., February 1, 2002; 8(2): 573 - 581. [Abstract] [Full Text] [PDF]