title: Increased vascular delivery and efficacy of chemotherapy after inhibition of platelet-derived growth factor-B.
abstract: Inhibition of platelet-derived growth factor-B (PDGF-B) has multiple effects on tumors, including loss of pericytes, regression of some vessels, normalization of other vessels, and reduction of interstitial pressure. PDGF-B inhibition also increases the efficacy of cancer therapeutics, but the role on tumor vessel efficiency and drug delivery is unclear. We sought to determine whether inhibition of PDGF-B signaling can increase delivery and efficacy of cyclophosphamide in Lewis lung carcinomas or RIP-Tag2 tumors. PDGF-B blockade in Lewis lung carcinoma tumors by the DNA aptamer AX102 for 14 days increased the number of perfused tumor vessels marked by lectin in the bloodstream by 50%. AX102 also increased the width of sleeves of viable tumor cells around blood vessels by 66%, increased tumor cell proliferation by 90%, and increased intratumoral delivery of Hoechst 33342 by 78%. A low dose of cyclophosphamide (20 mg/kg) reduced tumor cell proliferation by 31% when combined with AX102 but not when given alone. Synergy of cyclophosphamide and AX102 on tumor cell proliferation also was found in RIP-Tag2 tumors. Similarly, the PDGF receptor signaling inhibitor imatinib increased delivery of cyclophosphamide and reduced tumor burden in RIP-Tag2 mice, without evidence of tumor cell sensitization to chemotherapy. Together, these findings indicate that inhibition of PDGF-B signaling promotes the delivery and efficacy of chemotherapeutic agents by increasing the efficiency of tumor blood vessels.
authors.affiliation: Cardiovascular Research Institute, Comprehensive Cancer Center, Department of Anatomy, University of California, San Francisco, California, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Falcon
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.forename: Jeyling
authors.initials: J
authors.lastname: Chou
authors.forename: Debbie
authors.initials: D
authors.lastname: Chen
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001549:Benzamides; D001562:Benzimidazoles / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D001549:Benzamides; D001562:Benzimidazoles; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; C017807:bisbenzimide ethoxide trihydrochloride