Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2008 Jun 19

PMID 18559614

Citations 44

Authors

Arup Bhattacharya

Mukund Seshadri

Steven D Oven

Karoly Toth

Mary M Vaughan

Youcef M Rustum

Affiliations

Soon will be listed here.

Abstract

Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro. Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery in the observed therapeutic synergy in vivo.

Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d x 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/alpha-smooth muscle actin), perfusion (Hoechst 33342/DiOC7), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin using high-performance liquid chromatography and fluorescence microscopy.

Results: Double immunostaining of tumor sections revealed a marked reduction ( approximately 40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index ( approximately 30% > control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared with administration of doxorubicin alone.

Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation in vivo, and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo.

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References

Seshadri M, Mazurchuk R, Spernyak J, Bhattacharya A, Rustum Y, Bellnier D . Activity of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid against human head and neck carcinoma xenografts. Neoplasia. 2006; 8(7):534-42. PMC: 1601938. DOI: 10.1593/neo.06295. View

Miki K, Xu M, Gupta A, Ba Y, Tan Y, Bouvet M . Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate. Cancer Res. 2001; 61(18):6805-10. View

Jain R . Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001; 7(9):987-9. DOI: 10.1038/nm0901-987. View

Yin M, Li Z, Toth K, Cao S, Durrani F, Hapke G . Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced.... Oncogene. 2006; 25(17):2509-19. DOI: 10.1038/sj.onc.1209073. View

Fakih M, Pendyala L, Brady W, Smith P, Ross M, Creaven P . A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol. 2007; 62(3):499-508. DOI: 10.1007/s00280-007-0631-4. View

Primeau A, Rendon A, Hedley D, Lilge L, Tannock I . The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res. 2005; 11(24 Pt 1):8782-8. DOI: 10.1158/1078-0432.CCR-05-1664. View

Kakolyris S, Giatromanolaki A, Koukourakis M, Leigh I, Georgoulias V, Kanavaros P . Assessment of vascular maturation in non-small cell lung cancer using a novel basement membrane component, LH39: correlation with p53 and angiogenic factor expression. Cancer Res. 1999; 59(21):5602-7. View

Cristofanilli M, Charnsangavej C, Hortobagyi G . Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov. 2002; 1(6):415-26. DOI: 10.1038/nrd819. View

Cao S, Durrani F, Rustum Y . Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res. 2004; 10(7):2561-9. DOI: 10.1158/1078-0432.ccr-03-0268. View

10.

Dickson P, Hamner J, Sims T, Fraga C, Ng C, Rajasekeran S . Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007; 13(13):3942-50. DOI: 10.1158/1078-0432.CCR-07-0278. View

11.

Combs Jr G, Gray W . Chemopreventive agents: selenium. Pharmacol Ther. 1998; 79(3):179-92. DOI: 10.1016/s0163-7258(98)00014-x. View

12.

Clark L, Combs Jr G, Turnbull B, Slate E, Chalker D, Chow J . Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996; 276(24):1957-63. View

13.

Trotter M, Chaplin D, Olive P . Use of a carbocyanine dye as a marker of functional vasculature in murine tumours. Br J Cancer. 1989; 59(5):706-9. PMC: 2247238. DOI: 10.1038/bjc.1989.148. View

14.

Ruoslahti E . Specialization of tumour vasculature. Nat Rev Cancer. 2003; 2(2):83-90. DOI: 10.1038/nrc724. View

15.

Warner D, Burke T . Simple and versatile high-performance liquid chromatographic method for the simultaneous quantitation of the lactone and carboxylate forms of camptothecin anticancer drugs. J Chromatogr B Biomed Sci Appl. 1997; 691(1):161-71. DOI: 10.1016/s0378-4347(96)00426-4. View

16.

Fakih M, Pendyala L, Smith P, Creaven P, Reid M, Badmaev V . A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors. Clin Cancer Res. 2006; 12(4):1237-44. DOI: 10.1158/1078-0432.CCR-05-2004. View

17.

Jiang C, Jiang W, Ip C, Ganther H, Lu J . Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. Mol Carcinog. 1999; 26(4):213-25. DOI: 10.1002/(sici)1098-2744(199912)26:4<213::aid-mc1>3.0.co;2-z. View

18.

Tong R, Boucher Y, Kozin S, Winkler F, Hicklin D, Jain R . Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004; 64(11):3731-6. DOI: 10.1158/0008-5472.CAN-04-0074. View

19.

Bhattacharya A, Toth K, Mazurchuk R, Spernyak J, Slocum H, Pendyala L . Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy. Clin Cancer Res. 2004; 10(23):8005-17. DOI: 10.1158/1078-0432.CCR-04-1306. View

20.

Olive P . Radiation-induced reoxygenation in the SCCVII murine tumour: evidence for a decrease in oxygen consumption and an increase in tumour perfusion. Radiother Oncol. 1994; 32(1):37-46. DOI: 10.1016/0167-8140(94)90447-2. View