title: Inhibition of colon cancer growth by methylselenocysteine-induced angiogenic chemomodulation is influenced by histologic characteristics of the tumor.
abstract: Despite an armamentarium that is wide in range, scope of action, and target, chemotherapy has limited success in colorectal cancer (CRC). Novel approaches are needed to overcome tumor barriers to chemotherapy that includes an abnormal tumor vasculature constituting a poor drug delivery system. We have previously shown that 5-methylselenocysteine (MSC) enhances therapeutic efficacy of irinotecan in various human tumor xenografts. We have recently demonstrated that MSC through vascular normalization leads to better tumor vascular function in vivo. In this study, we examined the role of MSC on tumor vasculature, interstitial fluid pressure (IFP) and drug delivery in 2 histologically distinct CRC xenografts, HCT-8 (uniformly poorly differentiated) and HT-29 (moderately differentiated tumor with avascular glandular regions). The presence of specific histologic structures as a barrier to therapy in these xenografts and their clinical relevance was studied using tissue microarray of human surgical samples of CRC. MSC led to a significant tumor growth inhibition, a reduced microvessel density, and a more normalized vasculature in both colorectal xenografts. While IFP was found to be significantly improved in HCT-8, an improved intratumoral doxorubicin delivery seen in both xenografts could explain the observed increase in therapeutic efficacy. Differentiated, glandular, avascular and hypoxic regions that contribute to tumor heterogeneity in HT-29 were also evident in the majority of surgical samples of CRC. Such regions constitute a physical barrier to chemotherapy and can confer drug resistance. Our results indicate that MSC could enhance chemotherapeutic efficacy in human CRC, especially in CRC with few or no hypoxic regions.
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. arup.bhattacharya@roswellpark.org
authors.forename: Arup
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Károly
authors.initials: K
authors.lastname: Tóth
authors.forename: Arindam
authors.initials: A
authors.lastname: Sen
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.forename: Farukh A
authors.initials: FA
authors.lastname: Durrani
authors.forename: Erik
authors.initials: E
authors.lastname: Faber
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.forename: Youcef M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D002454:Cell Differentiation; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000473:pathology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000860:Hypoxia; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D017279:Selenocysteine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D016588:Anticarcinogenic Agents; D016566:Organoselenium Compounds; D017279:Selenocysteine; D004317:Doxorubicin; D003545:Cysteine; C002979:selenomethylselenocysteine