Determinants of paclitaxel penetration and accumulation in human solid tumor.

  • Kuh H
  • Jang S
  • Wientjes M
 et al. 
  • 49

    Readers

    Mendeley users who have this article in their library.
  • 119

    Citations

    Citations of this article.

Abstract

The present study examined the determinants of the penetration and accumulation of [(3)H]paclitaxel (12-12,000 nM) in three-dimensional histocultures of patient tumors and of a human xenograft tumor in mice. The results showed 1) significant and saturable drug accumulation in tumors, 2) extensive drug retention in tumors, and 3) a slower penetration but a more extensive accumulation in the xenograft tumor compared with patient tumors. Drug penetration was not rate-limited by drug diffusion from medium through the matrix supporting the histocultures. The difference in the expression of the mdr1 P-glycoprotein did not fully account for the difference in the drug accumulation in xenograft and patient tumors. Autoradiography and imaging were used to evaluate the spatial relationship between tumor architecture, tumor cell distribution, and drug distribution as a function of time and initial drug concentration in culture medium. The tumor cell density and the kinetics of drug-induced apoptosis were also evaluated. The results indicate that a high tumor cell density is a barrier to paclitaxel penetration and that the apoptotic effect of paclitaxel enhances its penetration in solid tumor. These factors are responsible for the time- and concentration-dependent drug penetration rate, with drug penetration confined to the periphery until apoptosis and reduction of epithelial cell density occurred at 24 h, after which time paclitaxel penetrated the inner parts of the tumor.

Author-supplied keywords

  • Animals
  • Antineoplastic Agents, Phytogenic
  • Antineoplastic Agents, Phytogenic: metabolism
  • Antineoplastic Agents, Phytogenic: pharmacokinetic
  • Autoradiography
  • Culture Techniques
  • Diffusion
  • Female
  • Half-Life
  • Head and Neck Neoplasms
  • Head and Neck Neoplasms: metabolism
  • Humans
  • Image Processing, Computer-Assisted
  • Mice
  • Neoplasms
  • Neoplasms: metabolism
  • Ovarian Neoplasms
  • Ovarian Neoplasms: metabolism
  • Paclitaxel
  • Paclitaxel: metabolism
  • Paclitaxel: pharmacokinetics
  • Pharyngeal Neoplasms
  • Pharyngeal Neoplasms: metabolism
  • Pharyngeal Neoplasms: pathology
  • Tissue Distribution
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • H J Kuh

  • S H Jang

  • M G Wientjes

  • J R Weaver

  • J L Au

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free