Increased vascular delivery and efficacy of chemotherapy after inhibition of platelet-derived growth factor-B

Am J Pathol. 2011 Jun;178(6):2920-30. doi: 10.1016/j.ajpath.2011.02.019.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Aptamers, Nucleotide / pharmacology
  • Benzamides
  • Benzimidazoles / metabolism
  • Carcinoma, Lewis Lung / blood supply*
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / pathology*
  • Cell Proliferation / drug effects
  • Cyclophosphamide / pharmacology
  • Cyclophosphamide / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems*
  • Drug Synergism
  • Imatinib Mesylate
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Pericytes / drug effects
  • Pericytes / pathology
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Proto-Oncogene Proteins c-sis / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-sis / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Aptamers, Nucleotide
  • Benzamides
  • Benzimidazoles
  • Piperazines
  • Proto-Oncogene Proteins c-sis
  • Pyrimidines
  • Imatinib Mesylate
  • Cyclophosphamide
  • bisbenzimide ethoxide trihydrochloride