Drug penetration in solid tumours

Minchinton, Andrew I.; Tannock, Ian F.

doi:10.1038/nrc1893

Cited by 2,805Drug Transport and Resistance MechanismsCancer Cells and MetastasisNanoparticle-Based Drug Delivery

Drug penetration in solid tumours

Minchinton, Andrew I., Tannock, Ian F.·2006·Nature reviews. Cancer

DOI 10.1038/nrc1893

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Abstract

To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concentration sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concentrated on molecular mechanisms of resistance, whereas the role of limited drug distribution within tumours has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumour tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue, thereby increasing the therapeutic index.

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The three-dimensional architecture of solid tumors presents significant challenges to the effective penetration and distribution of therapeutic agents.
“The three-dimensional (3D) architecture of solid tumors presents significant challenges to the effective penetration and distribution of therapeutic agents [99,100].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [99]
Drug distribution in tumors becomes reliant on diffusion alone, which is inefficient in the context of dense ECM and spatial heterogeneity characteristic of solid tumors.
“Consequently, drug distribution becomes reliant on diffusion alone, which is inefficient in the context of the dense ECM and spatial heterogeneity characteristic of solid tumors [99,154,155,156].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [99]
In tumors, inadequate lymphatic clearance causes fluid retention, elevating IFP and suppressing convective transport.
“In tumors, however, inadequate lymphatic clearance causes fluid retention, elevating IFP and suppressing convective transport [99,153].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [99]
Agents like paclitaxel, which preferentially target rapidly dividing cells, exhibit reduced cytotoxicity in the low-proliferation zones of tumor cores.
“Similarly, agents like paclitaxel, which preferentially target rapidly dividing cells, exhibit reduced cytotoxicity in the low-proliferation zones of tumor cores [99,113].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [99]
Penetration is governed by the physicochemical characteristics of the drug or particle-including size, surface charge, shape, lipophilicity, and acid dissociation constant-as well as by the structural and biochemical properties of the spheroid, such as ECM density, extracellular pH gradients, and compactness of the cellular arrangement.
“Penetration is governed by the physicochemical characteristics of the drug or particle—including size, surface charge, shape, lipophilicity, and acid dissociation constant—as well as by the structural and biochemical properties of the spheroid, such as ECM density, extracellular pH gradients, and compactness of the cellular arrangement [99,206,290].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [99]

The mathematics of diffusion
Crank, J. (1956) · CERN Document Server (European Organization for Nuclear Research) · Cited by 18,281 · see citing works
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968 · see citing works
Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer
Romond, E. H., Perez, E. A., Bryant, J., Suman, V. J., Geyer, C. E., Davidson, N. E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P. A., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa052122 · Cited by 5,355 · see citing works
Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177 · see citing works
Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer
Piccart-Gebhart, M. J., Procter, M., Leyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa052306 · Cited by 5,084 · see citing works
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784 · see citing works
Tumour stem cells and drug resistance
Dean, M., Fojo, T., & Bates, S. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1590 · Cited by 3,668 · see citing works
Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer
Vogel, C. L., Cobleigh, M., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L., Slamon, D. J., Murphy, M., Novotny, W. F., Burchmore, M., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.20.3.719 · Cited by 3,240 · see citing works
Exploiting tumour hypoxia in cancer treatment
Brown, J. M., & Wilson, W. R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1367 · Cited by 2,828 · see citing works
Molecular regulation of vessel maturation
Jain, R. K. (2003) · Nature Medicine · doi:10.1038/nm0603-685 · Cited by 2,515 · see citing works
Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.8.4607 · Cited by 2,438 · see citing works
The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy
Thomlinson, R. H., & Gray, L. H. (1955) · British Journal of Cancer · doi:10.1038/bjc.1955.55 · Cited by 2,228 · see citing works
High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy
Heldin, C.-H., Rubin, K., Pietras, K., & Östman, A. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1456 · Cited by 2,222 · see citing works
Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy
Jain, R. K. (2001) · Nature Medicine · doi:10.1038/nm0901-987 · Cited by 2,184 · see citing works
Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer
Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., Chung, D. C., Sahani, D. V., Kalva, S. P., Kozin, S. V., et al. (2004) · Nature Medicine · doi:10.1038/nm988 · Cited by 1,966 · see citing works
Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer
Vogel, C. L., Cobleigh, M. A., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L., Slamon, D. J., Murphy, M., Novotny, W. F., Burchmore, M., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.20.3.719 · Cited by 1,860 · see citing works
Cell and environment interactions in tumor microregions: the multicell spheroid model.
Sutherland, R. M. (1988) · Science · doi:10.1126/science.2451290 · Cited by 1,803 · see citing works
Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size.
Yuan, F., Dellian, M., Fukumura, D., Leunig, M., Berk, D. A., Torchilin, V. P., & Jain, R. K. (1995) · PubMed · Cited by 1,706 · see citing works
Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., & McDonald, D. M. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65006-7 · Cited by 1,689 · see citing works
Molecular imaging of cancer with positron emission tomography
Gambhir, S. S. (2002) · Nature reviews. Cancer · doi:10.1038/nrc882 · Cited by 1,658 · see citing works
Untitled work
(1989) · PubMed · Cited by 1,639 · see citing works
Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation
Helmlinger, G., Yuan, F., Dellian, M., & Jain, R. K. (1997) · Nature Medicine · doi:10.1038/nm0297-177 · Cited by 1,629 · see citing works
The unique physiology of solid tumors: opportunities (and problems) for cancer therapy.
Brown, J. M., & Giaccia, A. J. (1998) · PubMed · Cited by 1,498 · see citing works
Transport of molecules in the tumor interstitium: a review.
Jain, R. K. (1987) · PubMed · Cited by 1,357 · see citing works
Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors
Tong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0074 · Cited by 1,189 · see citing works
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation
Winkler, F., Kozin, S. V., Tong, R. T., Chae, S.-S., Booth, M. F., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., di Tomaso, E., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.10.011 · Cited by 1,170 · see citing works
Role of extracellular matrix assembly in interstitial transport in solid tumors.
Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J., & Jain, R. K. (2000) · PubMed · Cited by 1,165 · see citing works
Barriers to Drug Delivery in Solid Tumors
Jain, R. K. (1994) · Scientific American · doi:10.1038/scientificamerican0794-58 · Cited by 1,074 · see citing works
Tumor Vascular Permeability, Accumulation, and Penetration of Macromolecular Drug Carriers
Dreher, M. R., Liu, W., Michelich, C. R., Dewhirst, M. W., Yuan, F., & Chilkoti, A. (2006) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djj070 · Cited by 911 · see citing works
Cancer cells compress intratumour vessels
Padera, T. P., Stoll, B. R., Tooredman, J. B., Capen, D., Tomaso, E. D., & Jain, R. K. (2004) · Nature · doi:10.1038/427695a · Cited by 857 · see citing works
Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation
Brown, E. B., McKee, T. D., DiTomaso, E., Pluen, A., Seed, B., Boucher, Y., & Jain, R. K. (2003) · Nature Medicine · doi:10.1038/nm879 · Cited by 836 · see citing works
The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour
Tannock, I. F. (1968) · British Journal of Cancer · doi:10.1038/bjc.1968.34 · Cited by 763 · see citing works
Self-citation
Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages.
Poole, B., & Ohkuma, S. (1981) · The Journal of Cell Biology · doi:10.1083/jcb.90.3.665 · Cited by 753 · see citing works
Repopulation of cancer cells during therapy: an important cause of treatment failure
Kim, J. J., & Tannock, I. F. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1650 · Cited by 690 · see citing works
Self-citation
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiationRole of oxygenation, angiopoietin-1, and matrix metalloproteinases
WINKLER, F., Kozin, S. V., Tong, R. T., Chae, S.-K., Booth, M., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., & DiTomaso, E. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00305-8 · Cited by 685 · see citing works
Microvascular permeability of normal and neoplastic tissues
Gerlowski, L. E., & Jain, R. K. (1986) · Microvascular Research · doi:10.1016/0026-2862(86)90018-x · Cited by 623 · see citing works
Herceptin acts as an anti-angiogenic cocktail
Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D., & Jain, R. K. (2002) · Nature · doi:10.1038/416279b · Cited by 623 · see citing works
In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy
Brown, E. B., Campbell, R. B., Tsuzuki, Y., Xu, L., Carmeliet, P., Fukumura, D., & Jain, R. K. (2001) · Nature Medicine · doi:10.1038/89997 · Cited by 606 · see citing works
Dissecting tumour pathophysiology using intravital microscopy
Jain, R. K., Munn, L. L., & Fukumura, D. (2002) · Nature reviews. Cancer · doi:10.1038/nrc778 · Cited by 595 · see citing works
Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse.
Boucher, Y., & Jain, R. K. (1992) · PubMed · Cited by 510 · see citing works
Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions.
Less, J. R., Skalak, T. C., Sevick, E., & Jain, R. K. (1991) · PubMed · Cited by 508 · see citing works
Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy.
Tannock, I. F., Lee, C. M., Tunggal, J. K., Cowan, D., & Egorin, M. J. (2002) · PubMed · Cited by 505 · see citing works
Self-citation
The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors
Primeau, A. J., Rendon, A., Hedley, D., Lilge, L., & Tannock, I. F. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1664 · Cited by 499 · see citing works
Self-citation
Drug Delivery and Transport to Solid Tumors
Jang, S. H., Wientjes, M. G., Lü, D., & Au, J. L. ‐. (2003) · Pharmaceutical Research · doi:10.1023/a:1025785505977 · Cited by 491 · see citing works
Untitled work
(2000) · PubMed · Cited by 475 · see citing works
Intermittent blood flow in a murine tumor: radiobiological effects.
Chaplin, D. J., Olive, P. L., & Durand, R. E. (1987) · PubMed · Cited by 435 · see citing works
Tumor hypoxia: its impact on cancer therapy
Moulder, J. E., & Rockwell, S. (1987) · Cancer and Metastasis Reviews · doi:10.1007/bf00055376 · Cited by 413 · see citing works
Degradation of Fibrillar Collagen in a Human Melanoma Xenograft Improves the Efficacy of an Oncolytic Herpes Simplex Virus Vector
McKee, T. D., Grandi, P., Mok, W., Alexandrakis, G., Insin, N., Zimmer, J. P., Bawendi, M. G., Boucher, Y., Breakefield, X. O., & Jain, R. K. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2242 · Cited by 397 · see citing works
Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient
Mayer, L. D., Bally, M. B., & Cullis, P. R. (1986) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(86)90105-7 · Cited by 378 · see citing works
Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice.
Leunig, M., Yuan, F., Menger, M. D., Boucher, Y., Goetz, A. E., Meßmer, K., & Jain, R. K. (1992) · PubMed · Cited by 370 · see citing works
SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours
Brown, J. M. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.220 · Cited by 367 · see citing works
Untitled work
(1999) · PubMed · Cited by 348 · see citing works
Tumor Resistance to Alkylating Agents Conferred by Mechanisms Operative Only in Vivo
Teicher, B. A., Herman, T. S., Holden, S. A., Wang, Y., Pfeffer, M. R., Crawford, J. W., & Frei, E. (1990) · Science · doi:10.1126/science.2108497 · Cited by 327 · see citing works
Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies
Nyman, D. W., Campbell, K. J., Hersh, E. M., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2004.00.6148 · Cited by 286 · see citing works
Acquired multicellular-mediated resistance to alkylating agents in cancer.
Kobayashi, H., Man, S., Graham, C. H., Kapitain, S. J., Teicher, B. A., & Kerbel, R. S. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3294 · Cited by 277 · see citing works
Delivery of molecular and cellular medicine to solid tumors
Jain, R. K. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00027-6 · Cited by 272 · see citing works
Drug and radiation resistance in spheroids: cell contact and kinetics
Olive, P. L., & Durand, R. E. (1994) · Cancer and Metastasis Reviews · doi:10.1007/bf00689632 · Cited by 271 · see citing works
Delivery of Molecular and Cellular Medicine to Solid Tumors
Jain, R. K. (1997) · Microcirculation · doi:10.3109/10739689709148314 · Cited by 262 · see citing works
The Penetration of Anticancer Drugs through Tumor Tissue as a Function of Cellular Adhesion and Packing Density of Tumor Cells
Grantab, R., Sivananthan, S., & Tannock, I. F. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3077 · Cited by 254 · see citing works
Self-citation
Tirapazamine, Cisplatin, and Radiation Versus Fluorouracil, Cisplatin, and Radiation in Patients With Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02)
Rischin, D., Peters, L., Fisher, R., Macann, A., Denham, J., Poulsen, M., Jackson, M., Kenny, L., Penniment, M., Corry, J., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.072 · Cited by 253 · see citing works
Pharmacokinetics of adriamycin and tissue penetration in murine ovarian cancer.
Ozols, R. F., Locker, G. Y., Doroshow, J. H., Grotzinger, K. R., Myers, C. E., & Young, R. C. (1979) · PubMed · Cited by 248 · see citing works
Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker.
Raleigh, J. A., Calkins-Adams, D. P., Rinker, L. H., Ballenger, C. A., Weissler, M. C., Fowler, W. C., Novotny, D. B., & Varia, M. A. (1998) · PubMed · Cited by 242 · see citing works
Microenvironmental and cellular consequences of altered blood flow in tumours
Raghunand, N., Gatenby, R. A., & Gillies, R. J. (2003) · British Journal of Radiology · doi:10.1259/bjr/12913493 · Cited by 240 · see citing works
Endothelial-cell proliferation in experimental tumours
Denekamp, J., & Hobson, B. (1982) · British Journal of Cancer · doi:10.1038/bjc.1982.263 · Cited by 237 · see citing works
Radiation response of multicell spheroids--an in vitro tumour model.
Rm, S., & Re, D. (1976) · PubMed · Cited by 232 · see citing works
Resistance to adriamycin in multicellular spheroids
Sutherland, R. M., Eddy, H. A., Bareham, B. J., Reich, K., & Vanantwerp, D. (1979) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(79)90643-6 · Cited by 225 · see citing works
Cell kinetics and chemotherapy: a critical review.
Tannock, I. F. (1978) · PubMed · Cited by 224 · see citing works
Self-citation
Doxorubicin gradients in human breast cancer.
Lankelma, J., Dekker, H., Luque, R. F., Luykx, S., Hoekman, K., van der Valk, P., van Diest, P. J., & Pinedo, H. M. (1999) · PubMed · Cited by 215 · see citing works
Rescuing drug discovery: in vivo systems pathology and systems pharmacology
van der Greef, J., & McBurney, R. N. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1904 · Cited by 209 · see citing works
Phase I Trial of Concurrent Tirapazamine, Cisplatin, and Radiotherapy in Patients With Advanced Head and Neck Cancer
Rischin, D., Peters, L., Hicks, R. J., Hughes, P. G., Fisher, R., Hart, R., Sexton, M., D’Costa, I., & von Roemeling, R. (2001) · Journal of Clinical Oncology · doi:10.1200/jco.2001.19.2.535 · Cited by 199 · see citing works
Pegylated liposomal doxorubicin: Proof of principle using preclinical animal models and pharmacokinetic studies
Vail, D. M., Amantea, M., Colbern, G. T., Martin, F. J., Hilger, R. A., & Working, P. K. (2004) · Seminars in Oncology · doi:10.1053/j.seminoncol.2004.08.002 · Cited by 187 · see citing works
On the Access of Blood-Borne Dyes to Various Tumour Regions
Goldacre, R. J., & Sylvén, B. (1962) · British Journal of Cancer · doi:10.1038/bjc.1962.36 · Cited by 184 · see citing works
Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model.
Baxter, L. T., Zhu, H. J., Mackensen, D. G., Butler, W. F., & Jain, R. K. (1995) · PubMed · Cited by 179 · see citing works
Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)a cet amide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity
Koch, C., Evans, S. M., & Lord, E. (1995) · British Journal of Cancer · doi:10.1038/bjc.1995.426 · Cited by 178 · see citing works
Untitled work
(1972) · PubMed · Cited by 172 · see citing works
Omeprazole and bafilomycin, two proton pump inhibitors: Differentiation of their effects on gastric, kidney and bone H+-translocating ATPases
Mattsson, J. P., Väänänen, K., Wallmark, B., et al. (1991) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(91)90238-4 · Cited by 167 · see citing works
Determinants of Paclitaxel Penetration and Accumulation in Human Solid Tumor
Kuh, H., Jang, S. H., Wientjes, M. G., Weaver, J. R., & Au, J. L. ‐. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)34976-6 · Cited by 167 · see citing works
Targeted Anti–Vascular Endothelial Growth Factor Receptor-2 Therapy Leads to Short-term and Long-term Impairment of Vascular Function and Increase in Tumor Hypoxia
Franco, M., Man, S., Chen, L., Emmenegger, U., Shaked, Y., Cheung, A., Brown, A. S., Hicklin, D. J., Foster, F. S., & Kerbel, R. S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3295 · Cited by 162 · see citing works
Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy.
West, G. W., Weichselbaum, R. W., & Little, J. B. (1980) · PubMed · Cited by 155 · see citing works
Penetration and binding of radiolabeled anti-carcinoembryonic antigen monoclonal antibodies and their antigen binding fragments in human colon multicellular tumor spheroids.
Sutherland, R. M., Buchegger, F., Schreyer, M., Vacca, A., & Mach, J. (1987) · PubMed · Cited by 151 · see citing works
Examination by laser scanning confocal fluorescence imaging microscopy of the subcellular localisation of anthracyclines in parent and multidrug resistant cell lines
Coley, H., Amos, W., Twentyman, P. R., & Workman, P. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.244 · Cited by 147 · see citing works
TUMOUR CELL PROLIFERATION IN RELATION TO THE VASCULATURE
Hirst, D. G., & Denekamp, J. (1979) · Cell Proliferation · doi:10.1111/j.1365-2184.1979.tb00111.x · Cited by 140 · see citing works
Flow cytometry studies of intracellular adriamycin in multicell spheroids in vitro.
Durand, R. E. (1981) · PubMed · Cited by 133 · see citing works
Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors.
Tunggal, J. K., Cowan, D., Shaikh, H., & Tannock, I. F. (1999) · PubMed · Cited by 133 · see citing works
Self-citation
Bladder-cancer incidence in relation to vegetable and fruit consumption: A prospective study of atomic-bomb survivors
Nagano, J., Kono, S., Preston, D. L., Moriwaki, H., Sharp, G. B., Koyama, K., & Mabuchi, K. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000401)86:1 · Cited by 131 · see citing works
Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells
Davies, C. D. L., Berk, D. A., Pluen, A., & Jain, R. K. (2002) · British Journal of Cancer · doi:10.1038/sj.bjc.6600270 · Cited by 121 · see citing works
Use of Hoechst 33342 for cell selection from multicell systems.
Durand, R. E. (1982) · Journal of Histochemistry & Cytochemistry · doi:10.1177/30.2.6174559 · Cited by 119 · see citing works
Cell selection from a murine tumour using the fluorescent probe Hoechst 33342
Chaplin, D. J., Durand, R. E., & Olive, P. L. (1985) · British Journal of Cancer · doi:10.1038/bjc.1985.79 · Cited by 118 · see citing works
Cytofluorescence localization of adriamycin and daunorubicin.
Egorin, M. J., Hildebrand, R. C., Cimino, E. F., et al. (1974) · PubMed · Cited by 117 · see citing works
Imaging in Oncology, Second Edition
(2004) · CRC Press eBooks · doi:10.3109/9780203421314 · Cited by 113 · see citing works
Measurement of Material Extravasation in Microvascular Networks Using Fluorescence Video-Microscopy
Wu, N. Z., Klitzman, B. M., Rosner, G. L., et al. (1993) · Microvascular Research · doi:10.1006/mvre.1993.1049 · Cited by 111 · see citing works
Perivascular Oxygen Tensions in a Transplantable Mammary Tumor Growing in a Dorsal Flap Window Chamber
Dewhirst, M. W., Ong, E. T., Klitzman, B. M., Secomb, T. W., Vinuya, R. Z., Dodge, R. K., Brizel, D. M., & Gross, J. F. (1992) · Radiation Research · doi:10.2307/3578274 · Cited by 109 · see citing works
Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures.
Hicks, K. O., Pruijn, F. B., Sturman, J. R., Denny, W. A., & Wilson, W. R. (2003) · PubMed · Cited by 108 · see citing works
Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial.
Wishart, G. C., Bissett, D., Paul, J., Jodrell, D. I., Harnett, A. N., Habeshaw, T., Kerr, D. J., Macham, M. A., Soukop, M., & Leonard, R. C. (1994) · Journal of Clinical Oncology · doi:10.1200/jco.1994.12.9.1771 · Cited by 102 · see citing works
Extravascular diffusion of tirapazamine: effect of metabolic consumption assessed using the multicellular layer model
Hicks, K. O., Fleming, Y., Siim, B. G., Koch, C. J., & Wilson, W. R. (1998) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(98)00268-5 · Cited by 101 · see citing works
Characterization of Acidic Vesicles in Multidrug-resistant and Sensitive Cancer Cells by Acridine Orange Staining and Confocal Microspectrofluorometry
Millot, C., Millot, J., Morjani, H., Desplaces, A., & Manfait, M. (1997) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215549704500909 · Cited by 100 · see citing works
Inhibition of endosomal sequestration of basic anticancer drugs: influence on cytotoxicity and tissue penetration
Lee, C. M., & Tannock, I. F. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603010 · Cited by 98 · see citing works
Self-citation
Aspects of cytotoxic drug penetration, with particular reference to anthracyclines
Kerr, R. S., & Kaye, S. B. (1987) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00296245 · Cited by 94 · see citing works
Cytotoxicity of adriamycin in MGH-U1 cells grown as monolayer cultures, spheroids, and xenografts in immune-deprived mice.
Erlichman, C., & Vidgen, D. (1984) · PubMed · Cited by 94 · see citing works
Enhancement of Paclitaxel Delivery to Solid Tumors by Apoptosis-Inducing Pretreatment: Effect of Treatment Schedule
Jang, S. H., Wientjes, M. G., & Au, J. L. ‐. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38848-2 · Cited by 93 · see citing works
An experimental and mathematical model for the extravascular transport of a DNA intercalator in tumours
Hicks, K., Ohms, S., van Zijl, P. L., Denny, W. A., Hunter, P. J., & Wilson, W. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.481 · Cited by 92 · see citing works
Informed consent in the childrens cancer group
Childrens Cancer Group, Kodish, E. D., Pentz, R. D., Noll, R. B., Ruccione, K., Buckley, J. D., & Lange, B. J. (1998) · Cancer · doi:10.1002/(sici)1097-0142(19980615)82:12 · Cited by 91 · see citing works
Multicellular membranes as an in vitro model for extravascular diffusion in tumours.
Cowan, D., Hicks, K. O., & Wilson, W. R. (1996) · PubMed · Cited by 85 · see citing works
Penetration of substances into tumor tissue—A methodological study on cellular spheroids
Nederman, T., Carlsson, J., & Malmqvist, M. (1981) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02618140 · Cited by 84 · see citing works
Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors
Croix, B. S., Man, S., & Kerbel, R. S. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00199-2 · Cited by 82 · see citing works
Direct Assessment of Drug Penetration into Tissue Using a Novel Application of Three-Dimensional Cell Culture
Kyle, A. H., Huxham, L. A., Chiam, A. S. J., Sim, D. H., & Minchinton, A. I. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1099 · Cited by 81 · see citing works
Self-citation
Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours
Phillips, R. M., Loadman, P. M., & Cronin, B. (1998) · British Journal of Cancer · doi:10.1038/bjc.1998.355 · Cited by 81 · see citing works
Microregional Effects of Gemcitabine in HCT-116 Xenografts
Huxham, L. A., Kyle, A. H., Baker, J. H. E., Nykilchuk, L. K., & Minchinton, A. I. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0986 · Cited by 79 · see citing works
Self-citation
Chemosensitivity Testing in V79 Spheroids: Drug Delivery and Cellular Microenvironment 2
Durand, R. E. (1986) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/77.1.247 · Cited by 78 · see citing works
Penetration and binding of vinblastine and 5-fluorouracil in cellular spheroids
Nederman, T., & Carlsson, J. (1984) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00257130 · Cited by 78 · see citing works
Relations between the penetration, binding and average concentration of cytostatic drugs in human tumour spheroids
Erlanson, M., Daniel-Szolgay, E., & Carlsson, J. (1992) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00686002 · Cited by 77 · see citing works
Measurement of delivery and metabolism of tirapazamine to tumour tissue using the multilayered cell culture model
Kyle, A. H., & Minchinton, A. I. (1999) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800050886 · Cited by 76 · see citing works
Self-citation
Slow penetration of anthracyclines into spheroids and tumors: a therapeutic advantage?
Durand, R. E. (1990) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf02897199 · Cited by 76 · see citing works
Variable Radiobiological Responses of Spheroids
Durand, R. E. (1980) · Radiation Research · doi:10.2307/3575364 · Cited by 73 · see citing works
A Rapid Method for studying Tumour Blood Supply using Systemic Dyes
Goldacre, R. J., & Sylvén, B. (1959) · Nature · doi:10.1038/184063a0 · Cited by 70 · see citing works
A randomised clinical study of verapamil in addition to combination chemotherapy in small cell lung cancer
Milroy, R. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.433 · Cited by 68 · see citing works
Temporal changes in pO2 of R3230Ac tumors in fischer-344 rats
Dewhirst, M. W., Braun, R. D., & Lanzen, J. L. (1998) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(98)00304-6 · Cited by 68 · see citing works
Immunocytochemical detection of interaction products of cis-diamminedichloroplatinum(II) and cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) with DNA in rodent tissue sections.
Terheggen, P. M. A. B., Floot, B. G. J., Scherer, E., et al. (1987) · PubMed · Cited by 65 · see citing works
Dynamics of microvascular flow in implanted mouse mammary tumours.
Intaglietta, M., Myers, R. R., Gross, J. F., & Reinhold, H. S. (1977) · PubMed · Cited by 61 · see citing works
A Kinin in Apple Fruitlets
Goldacre, P., & Bottomley, W. (1959) · Nature · doi:10.1038/184555a0 · Cited by 59 · see citing works
Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors.
Rs, K., St Croix, B., Va, F., & Rak, J. (1996) · PubMed · Cited by 59 · see citing works
Extravascular Transport of Drugs in Tumor Tissue: Effect of Lipophilicity on Diffusion of Tirapazamine Analogues in Multicellular Layer Cultures
Pruijn, F. B., Sturman, J. R., Liyanage, H. D. S., Hicks, K. O., Hay, M. P., & Wilson, W. R. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049549p · Cited by 56 · see citing works
Ionizing Radiation Antagonizes Tumor Hypoxia Induced by Antiangiogenic Treatment
Riesterer, O., Honer, M., Jochum, W., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2816 · Cited by 55 · see citing works
Intermittent blood flow in the KHT sarcoma--flow cytometry studies using Hoechst 33342
Minchinton, A. I., Durand, R. E., & Chaplin, D. J. (1990) · British Journal of Cancer · doi:10.1038/bjc.1990.259 · Cited by 53 · see citing works
Self-citation
Multilayers of Cells Growing on a Permeable Support: An in Vitro Tumour Model
Minchinton, A. I., Wendt, K. R., Clow, K. A., & Fryer, K. H. (1997) · Acta Oncologica · doi:10.3109/02841869709100724 · Cited by 51 · see citing works
Self-citation
Variability of tumor response to chemotherapy II. Contribution of tumor heterogeneity
Simpson‐Herren, L., Noker, P. E., & Wagoner, S. D. (1988) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00257310 · Cited by 47 · see citing works
NCI's anticancer drug screening program may not be selecting for clinically active compounds.
Brown, J. M. (1997) · PubMed · Cited by 46 · see citing works
Oxygen Dependence of the Metabolic Activation and Cytotoxicity of Tirapazamine: Implications for Extravascular Transport andActivity in Tumors
Hicks, K. O., Siim, B. G., Pruijn, F. B., & Wilson, W. R. (2004) · Radiation Research · doi:10.1667/rr3178 · Cited by 46 · see citing works
Resistance to vincristine of human cells grown as multicellular spheroids
Wibe, E. (1980) · British Journal of Cancer · doi:10.1038/bjc.1980.344 · Cited by 43 · see citing works
Extravascular Transport of the DNA Intercalator and Topoisomerase PoisonN-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA): Diffusion and Metabolism in Multicellular Layers of Tumor Cells
Hicks, K. O., Pruijn, F. B., Baguley, B. C., & Wilson, W. R. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29637-3 · Cited by 42 · see citing works
Identification of genes differentially expressed in V79 cells grown as multicell spheroids
Oloumi, A., Lam, W. L., Banáth, J. P., et al. (2002) · International Journal of Radiation Biology · doi:10.1080/09553000210122299 · Cited by 38 · see citing works
Cytotoxic drug penetration studies in multicellular tumour spheroids
Kerr, D. J., Wheldon, T. E., Hydns, S., et al. (1988) · Xenobiotica · doi:10.3109/00498258809041702 · Cited by 36 · see citing works
Mass Transport in Tumors: Characterization and Applications to Chemotherapy
Jain, R. K., Weissbrod, J. M., & Wel, J. (1980) · Advances in cancer research · doi:10.1016/s0065-230x(08)60672-7 · Cited by 29 · see citing works
Preclinical toxicological testing and safeguards in clinical trials
Smith, A. D. (1982) · European Journal of Clinical Pharmacology · doi:10.1007/bf00606417 · Cited by 29 · see citing works
Measurement of extravascular drug diffusion in multicellular layers.
Wilson, W. R., & Ko, H. (1999) · PubMed · Cited by 27 · see citing works
Tumor distribution of bromodeoxyuridine-labeled cells is strongly dose dependent.
Kyle, A. H., Huxham, L. A., Baker, J. H. E., et al. (2003) · PubMed · Cited by 25 · see citing works
Evidence for intermittent radiobiological hypoxia in experimental tumour systems.
Chaplin, D. J., Trotter, M. J., Durand, R. E., Olive, P. L., & Minchinton, A. I. (1989) · PubMed · Cited by 23 · see citing works
Self-citation
Effect of the Selective Estrogen Receptor Modulator Arzoxifene on Repopulation of Hormone-Responsive Breast Cancer Xenografts between Courses of Chemotherapy
Wu, L., & Tannock, I. F. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1258 · Cited by 22 · see citing works
Self-citation
Immunocytochemical analysis of cisplatin-induced platinum-DNA adducts with double-fluorescence video microscopy
Meijer, C., de Vries, E. G. E., Dam, W., et al. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.381 · Cited by 19 · see citing works
Tirapazamine causes vascular dysfunction in HCT-116 tumour xenografts
Huxham, L. A., Kyle, A. H., Baker, J. H. E., et al. (2006) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2006.01.002 · Cited by 18 · see citing works
Reproducibility of measurements of potential doubling time of tumour cells in the multicentre National Cancer Institute protocol T92-0045
Wilson, G. D., Paschoud, N., Pavy, J., Weber, K., Weber, P., Dubray, B. M., & Coucke, P. A. (1998) · British Journal of Cancer · doi:10.1038/sj.bjc.6690052 · Cited by 17 · see citing works
In vivo labelling with halogenated pyrimidines of squamous cell carcinomas and adjacent non‐involved mucosa of head and neck region
Kotelnikov, V. M., Coon, J. S., Taylor, S., et al. (1995) · Cell Proliferation · doi:10.1111/j.1365-2184.1995.tb00088.x · Cited by 15 · see citing works
Diversity of penetration of anti‐cancer agents into solid tumours
Simpson‐Herren, L., & Noker, P. E. (1991) · Cell Proliferation · doi:10.1111/j.1365-2184.1991.tb01164.x · Cited by 15 · see citing works
Pharmacokinetic studies of mitoxantrone and one of its metabolites in serum and urine in patients with advanced breast cancer
Rentsch, K. M., Schwendener, R. A., Pestalozzi, B. C., et al. (1998) · European Journal of Clinical Pharmacology · doi:10.1007/s002280050425 · Cited by 13 · see citing works
Differential penetration of targeting agents into multicellular spheroids derived from human neuroblastoma.
Mairs, R., Angerson, W. J., Babich, J. W., & Murray, T. J. (1991) · PubMed · Cited by 11 · see citing works
Visualisation of doxorubicin in human and animal tissues and in cell cultures by immunogold-silver staining
Henneberry, H., & Aherne, G. W. (1992) · British Journal of Cancer · doi:10.1038/bjc.1992.15 · Cited by 11 · see citing works
Immunocytochemical localisation of VP16-213 in normal and malignant tissues
Henneberry, H. P., Aherne, G. W., & Marks, V. (1987) · Cancer Letters · doi:10.1016/0304-3835(87)90166-2 · Cited by 5 · see citing works
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Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170 · see citing works
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Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172 · see citing works
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Vasan, N., Baselga, J., & Hyman, D. M. (2019) · Nature · doi:10.1038/s41586-019-1730-1 · Cited by 2,770 · see citing works
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Sun, T., Zhang, Y. S., Pang, B., Hyun, D. C., Yang, M., & Xia, Y. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201403036 · Cited by 2,164 · see citing works
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Tredan, O., Galmarini, C. M., Patel, K., & Tannock, I. F. (2007) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djm135 · Cited by 2,116 · see citing works
Self-citation
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Friedrich, J., Seidel, C., Ebner, R., & Kunz-Schughart, L. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.226 · Cited by 1,742 · see citing works
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Liechty, W. B., Kryscio, D. R., Slaughter, B. V., & Peppas, N. A. (2010) · Annual Review of Chemical and Biomolecular Engineering · doi:10.1146/annurev-chembioeng-073009-100847 · Cited by 1,608 · see citing works
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Danhier, F. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.11.015 · Cited by 1,288 · see citing works
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Zanoni, M., Piccinini, F., Arienti, C., Zamagni, A., Santi, S., Polico, R., Bevilacqua, A., & Tesei, A. (2016) · Scientific Reports · doi:10.1038/srep19103 · Cited by 1,144 · see citing works
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Bumbaca, D., Boswell, C. A., Fielder, P. J., & Khawli, L. A. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9369-y · Cited by 119 · see citing works
TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules
Liu, Q., Sun, J. D., Wang, J., Ahluwalia, D., Baker, A. F., Cranmer, L. D., Ferraro, D., Wang, Y., Duan, J.-X., Ammons, W. S., et al. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-012-1852-8 · Cited by 113 · see citing works
MMP-2 responsive polymeric micelles for cancer-targeted intracellular drug delivery
Chen, W.-H., Luo, G.-F., Lei, Q., Jia, H.-Z., Hong, S., Wang, Q.-R., Zhuo, R.-X., & Zhang, X.-Z. (2015) · Chemical Communications · doi:10.1039/c4cc07563c · Cited by 115 · see citing works
Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells
Vilgelm, A. E., Pawlikowski, J. S., Liu, Y., Hawkins, O. E., Davis, T. A., Smith, J., Weller, K. P., Horton, L. W., McClain, C. M., Ayers, G. D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2405 · Cited by 115 · see citing works
Application of Concave Microwells to Pancreatic Tumor Spheroids Enabling Anticancer Drug Evaluation in a Clinically Relevant Drug Resistance Model
Yeon, S.-E., No, D. Y., Lee, S.-H., Nam, S. W., Oh, I.-H., Lee, J., & Kuh, H.-J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073345 · Cited by 110 · see citing works
Quantitating drug-target engagement in single cells in vitro and in vivo
Dubach, J. M., Kim, E., Yang, K., Cuccarese, M., Giedt, R. J., Meimetis, L. G., Vinegoni, C., & Weissleder, R. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2248 · Cited by 87 · see citing works
Hyperbaric Oxygen Boosts PD‐1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors
Liu, X., Ye, N., Liu, S., Guan, J., Deng, Q., Zhang, Z., Xiao, C., Ding, Z., Zhang, B., Chen, X., et al. (2021) · Advanced Science · doi:10.1002/advs.202100233 · Cited by 83 · see citing works
The current landscape of 3D in vitro tumor models: what cancer hallmarks are accessible for drug discovery?
Rodenhizer, D., Dean, T., D'Arcangelo, E., & McGuigan, A. P. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201701174 · Cited by 80 · see citing works
Polymeric micelles for enhanced lymphatic drug delivery to treat metastatic tumors
Qin, L., Zhang, F., Lu, X., Wei, X., Wang, J., Fang, X., Si, D., Wang, Y., Zhang, C., Yang, R., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.07.005 · Cited by 80 · see citing works
Nanoparticles Penetrate into the Multicellular Spheroid-on-Chip: Effect of Surface Charge, Protein Corona, and Exterior Flow
Huang, K., Boerhan, R., Liu, C., & Jiang, G. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b00726 · Cited by 74 · see citing works
Assessing the in Vivo Efficacy of Doxorubicin Loaded Hyaluronan Nanoparticles
El-Dakdouki, M. H., Xia, J., Zhu, D. C., Kavunja, H., Grieshaber, J., O’Reilly, S., McCormick, J. J., & Huang, X. (2014) · ACS Applied Materials & Interfaces · doi:10.1021/am404946v · Cited by 69 · see citing works
Changes in Global Gene Expression Associated with 3D Structure of Tumors: An Ex Vivo Matrix-Free Mesothelioma Spheroid Model
Kim, H., Phung, Y., & Ho, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039556 · Cited by 68 · see citing works
Spatial heterogeneity of nanomedicine investigated by multiscale imaging of the drug, the nanoparticle and the tumour environment
de Maar, J. S., Sofias, A. M., Porta Siegel, T., Vreeken, R. J., Moonen, C., Bos, C., & Deckers, R. (2020) · Theranostics · doi:10.7150/thno.38625 · Cited by 71 · see citing works
Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis
Shah, S., & D’Souza, G. G. M. (2025) · Cells · doi:10.3390/cells14100732 · Cited by 66 · see citing works
“Similarly, agents like paclitaxel, which preferentially target rapidly dividing cells, exhibit reduced cytotoxicity in the low-proliferation zones of tumor cores [99,113].”
Influential
Modeling of cancer metastasis and drug resistance via biomimetic nano-cilia and microfluidics
Kuo, C.-T., Chiang, C.-L., Chang, C.-H., Liu, H.-K., Huang, G.-S., Huang, R. Y.-J., Lee, H., Huang, C.-S., & Wo, A. M. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2013.11.008 · Cited by 65 · see citing works
Hypoxia-inducible factors as key regulators of tumor inflammation
Mamlouk, S., & Wielockx, B. (2013) · International Journal of Cancer · doi:10.1002/ijc.27901 · Cited by 61 · see citing works
Synthetic tumor networks for screening drug delivery systems
Prabhakarpandian, B., Shen, M.-C., Nichols, J. B., Garson, C. J., Mills, I. R., Matar, M. M., Fewell, J. G., & Pant, K. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.01.018 · Cited by 57 · see citing works
A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening
Heylman, C., Sobrino, A., Shirure, V. S., Hughes, C. C., & George, S. C. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214525295 · Cited by 53 · see citing works
The Development and Characterization of a Human Mesothelioma In Vitro 3D Model to Investigate Immunotoxin Therapy
Xiang, X., Phung, Y., Feng, M., Nagashima, K., Zhang, J., Broaddus, V. C., Hassan, R., FitzGerald, D., & Ho, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014640 · Cited by 51 · see citing works
Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening
Wang, J.-Z., Zhu, Y.-X., Ma, H.-C., Chen, S.-N., Chao, J.-Y., Ruan, W.-D., Wang, D., Du, F.-G., & Meng, Y.-Z. (2016) · Materials Science and Engineering: C · doi:10.1016/j.msec.2016.01.045 · Cited by 49 · see citing works
Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue
Kuiper, C., Vissers, M. C. M., & Hicks, K. O. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.09.023 · Cited by 45 · see citing works
Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer
Devarasetty, M., Skardal, A., Cowdrick, K., Marini, F., & Soker, S. (2017) · Tissue Engineering Part A · doi:10.1089/ten.tea.2017.0397 · Cited by 41 · see citing works
Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine
Kirtane, A. R., Sadhukha, T., Kim, H., Khanna, V., Koniar, B., & Panyam, J. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-1646 · Cited by 38 · see citing works
The use of spectroscopic imaging and mapping techniques in the characterisation and study of DLD-1 cell spheroid tumour models
Zhang, J. Z., Bryce, N. S., Siegele, R., Carter, E. A., Paterson, D., de Jonge, M. D., Howard, D. L., Ryan, C. G., & Hambley, T. W. (2012) · Integrative Biology · doi:10.1039/c2ib20121f · Cited by 37 · see citing works
Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier
Yokoi, K., Chan, D., Kojic, M., Milosevic, M., Engler, D., Matsunami, R., Tanei, T., Saito, Y., Ferrari, M., & Ziemys, A. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.044 · Cited by 36 · see citing works
Tumor microenvironment determines response to a heat-activated thermosensitive liposome formulation of cisplatin in cervical carcinoma
Dou, Y. N., Chaudary, N., Chang, M. C., Dunne, M., Huang, H., Jaffray, D. A., Milosevic, M., & Allen, C. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.07.039 · Cited by 21 · see citing works

Authors: Minchinton, A. I., & Tannock, I. F.
Affiliations: BC Cancer Agency (CA)
University of Toronto (CA)
Corresponding author: Minchinton, Andrew I.
Tannock, Ian F.
ORCID: Minchinton, Andrew I.
Tannock, Ian F.
Venue: Nature reviews. Cancer
Publisher: Springer Science and Business Media LLC
Published: 2006-08
Volume: 6
Issue: 8
Pages: 583-592
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc1893
OpenAlex: W2079142824
Cited by: 2,805
References: 148
Citations by year: 2026: 128 · 2025: 113 · 2024: 123 · 2023: 136 · 2022: 134 · 2021: 212 · 2020: 202 · 2019: 182 · 2018: 195 · 2017: 200 · 2016: 194 · 2015: 174 · 2014: 159 · 2013: 170 · 2012: 130
FWCI: 5.58
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords: drug penetration, solid tumors, chemoresistance, drug delivery methods, therapeutic index, tumor heterogeneity
MeSH terms: Animals, Antineoplastic Agents, Humans, Neoplasms, Tumor Cells, Cultured, Drug Delivery Systems, Spheroids, Cellular, Drug Resistance, Neoplasm

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