Clinical aspects of drug delivery to tumors

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Abstract

This report describes our experience on enhancement of drug delivery to solid tumors. Results of our preclinical and clinical studies including a randomized prospective phase III trial have validated the concept that enhanced drug delivery can significantly improve the treatment efficacy of intravesical mitomycin C therapy of superficial bladder cancer. The report further describes the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. The transport of highly protein-bound drugs such as paclitaxel and doxorubicin in a solid tumor is retarded by a high tumor cell density and enhanced by drug-induced apoptosis. Results of in vitro studies using solid tumor histocultures and in vivo studies using tumor-bearing animals demonstrate that the delivery of highly protein-bound drugs to tumor can be enhanced using a pretreatment that induces apoptosis and reduces cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition.

Introduction

This report describes our experience on enhancement of drug delivery to solid tumors. The first part describes a study where pharmacokinetic interventions designed to enhance drug delivery during intravesical therapy resulted in enhanced treatment efficacy in superficial bladder cancer patients. The second part addresses the barriers and determinants on the delivery of highly protein-bound drugs to solid tumors and describes an experimental approach where apoptosis-inducing pretreatment resulted in enhanced drug delivery.

Section snippets

Intravesical therapy in superficial bladder cancer

Approximately 70–80% of bladder cancer patients present with superficial tumors (i.e. Ta tumors located in the urothelium, T1 tumors located in the lamina propria, and/or carcinoma in situ (Tis)). Transurethral resection is the primary treatment, and 40–80% of patients treated only by this procedure develop tumor recurrence. Recurrent tumors may result from growth of occult unresected tumor, implantation of tumor cells into denuded surfaces during resection, and/or de novo tumor formation from

Determinants of drug distribution in solid tumors

Many anticancer drugs exert their action by binding to macromolecules and show high binding to proteins including the plasma proteins. Earlier studies using tumor cell spheroids have shown that penetration of protein-binding drugs such as doxorubicin and paclitaxel is limited to the periphery [13], [14], [15], [16], [17]. We have conducted a series of studies to identify the determinations of distribution of protein-bound drugs in solid tumors. These studies were performed using in vitro

Conclusions

We have demonstrated that enhancement of drug delivery to solid tumor results in improved efficacy of intravesical MMC therapy in the treatment of superficial bladder cancer. We further demonstrate an experimental approach which takes advantage of the apoptosis-induction effect of paclitaxel and doxorubicin to enhance the delivery of protein-bound drugs to solid tumors. Because drug-induced apoptosis is a dynamic process, the delivery of these drugs to cells in a solid tumor is also a dynamic

Acknowledgements

The work described in this study is partly supported by research grants R37CA49816, R01CA53983, R01CA58988, R01CA58989, R01CA63363 and R01CA74179 from the National Cancer Institute, NIH, DHHS.

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