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Time-and concentration-dependent penetration of doxorubicin in prostate tumors

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Abstract

The penetration of paclitaxel into multilayered solid tumors is time- and concentration-dependent, a result of the drug-induced apoptosis and changes in tissue composition. This study evaluates whether this tissue penetration property applies to other highly protein-bound drugs capable of inducing apoptosis. The penetration of doxorubicin was studied in histocultures of prostate xenograft tumors and tumor specimens obtained from patients who underwent radical prostatectomy. The kinetics of drug uptake and efflux in whole tumor histocultures were studied by analyzing the average tumor drug concentration using high-pressure liquid chromatography. Spatial drug distribution in tumors and the drug concentration gradient across the tumors were studied using fluorescence microscopy. The results indicate that drug penetration was limited to the periphery for 12 hours in patient tumors and to 24 hours in the more densely packed xenograft tumors. Subsequently, the rate of drug penetration to the deeper tumor tissue increased abruptly in tumors treated with higher drug concentrations capable of inducing apoptosis (i.e., >5 μm), but not in tumors treated with lower concentrations. These findings indicate a time- and concentration-dependent penetration of doxorubicin in solid tumors, similar to that of paclitaxel. We conclude that doxorubicin penetration in solid tumors is time- and concentration-dependent and is enhanced by drug-induced cell death.

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Author notes

  1. Jenny H. Zheng

    Present address: Food and Drug Administration, 9201 Corporate Blvd, HFD-880, 20850, Rockville, MD

  2. Chiung-Tong Chen

    Present address: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 1F, Building C, 103, Lane 169 Kang-Ning Street. Hsi-Chih, 221, Taipei, Taiwan

Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, OH

    Jenny H. Zheng, Chiung-Tong Chen, Jessie L. S. Au & M. Guill Wientjes

  2. James Cancer Hospital and Solove Research Institute, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, OH

    Jenny H. Zheng, Chiung-Tong Chen, Jessie L. S. Au & M. Guill Wientjes

Authors
  1. Jenny H. Zheng
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  2. Chiung-Tong Chen
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  3. Jessie L. S. Au
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  4. M. Guill Wientjes
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Correspondence to M. Guill Wientjes.

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Published: May 15, 2001.

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Zheng, J.H., Chen, CT., Au, J.L.S. et al. Time-and concentration-dependent penetration of doxorubicin in prostate tumors. AAPS PharmSci 3, 15 (2001). https://doi.org/10.1208/ps030215

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  • DOI: https://doi.org/10.1208/ps030215

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