The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid Tumors

Purpose: Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice. Experimental Design: The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5. Results: The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 μm, The mean distance from blood vessels to regions of hypoxia is 90 to 140 μm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection. Conclusions: Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution.

[1]  R. Jain,et al.  Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. , 1991, Cancer research.

[2]  R. Jain.  The next frontier of molecular medicine: Delivery of therapeutics , 1998, Nature Medicine.

[3]  A. Minchinton,et al.  Microregional Effects of Gemcitabine in HCT-116 Xenografts , 2004, Cancer Research.

[4]  A J Davis,et al.  Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. , 2000, The Lancet. Oncology.

[5]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[6]  A. Vandewalle,et al.  Inhibitors of vacuolar H+-ATPase impair the preferential accumulation of daunomycin in lysosomes and reverse the resistance to anthracyclines in drug-resistant renal epithelial cells. , 2003, The Biochemical journal.

[7]  F. Bianchi,et al.  Comparative activity of doxorubicin and its major metabolite, doxorubicinol, on V79/AP4 fibroblasts: a morphofunctional study. , 1991, Experimental and molecular pathology.

[8]  P. Hunter,et al.  An experimental and mathematical model for the extravascular transport of a DNA intercalator in tumours. , 1997, British Journal of Cancer.

[9]  Ian F Tannock,et al.  Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  I. Tannock,et al.  Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  R. Kerbel,et al.  Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors. , 1996, Human cell.

[12]  J. Romijn.  Growth of tumor cells with different sensitivities for murine natural killer cells in young and adult athymic nude mice. , 1985, Experimental cell biology.

[13]  B Vojnovic,et al.  Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells. , 2005, Advanced drug delivery reviews.

[14]  R. Sutherland,et al.  Resistance to adriamycin in multicellular spheroids. , 1979, International journal of radiation oncology, biology, physics.

[15]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[16]  Lei Xu,et al.  Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. , 2004, Cancer cell.

[17]  J. Lankelma,et al.  Doxorubicin gradients in human breast cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  R. Kerbel,et al.  Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors. , 1998, Cancer letters.