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The Basis of Regional Therapy, Pharmacology, Hyperthermia, and Drug Resistance

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Cancer Regional Therapy

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Abstract

The peritoneal surface is a common failure site for gastrointestinal and gynecologic tumors. For chemotherapeutic agents to effectively kill malignant cells in peritoneal implants, agents must first reach the target. The inability of the drug to reach the target is a basic mechanism of drug resistance. Chemotherapy delivered intravenously encounters the following resistances: (a) distribution through vascular space, (b) transport across microvascular wall, (c) transport through the interstitial space, (d) transport across the cell membrane, and (e) actual incorporation. This last step is complicated by the low vascularization of the peritoneum. The intraperitoneal route seems more logical as this route bypasses the first compartment, and the peritoneal cavity can absorb almost all agents and mediates the transfer of intraperitoneally administered chemotherapy, with agents entering the systemic circulation either by diffusion into the vascular compartment or by absorption through peritoneal lymphatics. In addition, the peritoneal-plasma barrier allows dose intensification providing high concentrations of the therapeutic agent while minimizing systemic toxicity. Traditionally, the selection of drugs for intraperitoneal administration has been based on beneficial pharmacokinetic and pharmacodynamic parameters, a good tolerance profile, and proven effectiveness with systemic administration. However, the process appears to be more complex. In this chapter, we will discuss how the tumor microenvironment plays a crucial role and the effects of hyperthermia, try to understand the molecular basis of drug effectiveness/resistance at the gene as well as the protein level, and explain why high concentrations of the therapeutic agent at the level of the tumor do not necessarily translate into greater efficacy.

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Authors and Affiliations

  1. Ziehenhuis Oost Limberg, Department of Surgical Oncology, Genk, Limberg, Belgium

    Kim Govaerts & Kurt Van der Speeten

  2. Universiteit Hasselt, Department of Life Sciences, BIOMED Research Institute, Hasselt, Belgium

    Kurt Van der Speeten

  3. Virginia Commonwealth University School of Medicine, Inova Fairfax Medical Campus, Department of Surgery, Falls Church, VA, USA

    Lana Bijelic

  4. Frederick Memorial Hospital, Department of Surgery, Division of Surgical Oncology, Frederick, MD, USA

    Jesus Esquivel

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  1. Kim Govaerts
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  2. Kurt Van der Speeten
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  3. Lana Bijelic
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  4. Jesus Esquivel
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Editors and Affiliations

  1. City Of Hope National Medical Center, Duarte, CA, USA

    Yuman Fong

  2. Medical College of Wisconsin, Milwaukee, WI, USA

    T. Clark Gamblin

  3. City Of Hope National Medical Center, Duarte, CA, USA

    Ernest S. Han

  4. City Of Hope National Medical Center, Duarte, CA, USA

    Byrne Lee

  5. Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Jonathan S. Zager

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Govaerts, K., Van der Speeten, K., Bijelic, L., Esquivel, J. (2020). The Basis of Regional Therapy, Pharmacology, Hyperthermia, and Drug Resistance. In: Fong, Y., Gamblin, T., Han, E., Lee, B., Zager, J. (eds) Cancer Regional Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-28891-4_1

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