Perspective
Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy

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Abstract

Whole Body Hyperthermia (WBH) enhancement of chemotherapy and/or radiation without a concomitant increase in myelosuppression has been documented in clinical trials. We propose that the biological basis for this phenomena relates in part to the previously reported induction of peripheral cytokines by WBH, that is, granulocyte colony stimulating factor (G-CSF), interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and the regulatory cytokine IL-10. To further explain this myeloprotection and the additional clinical observation that WBH promotes early engraftment of bone marrow (when used as part of an allogenic bone marrow transplant preconditioning regimen) we developed a hypothesis: WBH increases peripheral IL-1β, IL-6, and TNF-α resulting in a secondary induction of IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF) in the bone marrow, for which supportive data also exists. Taken collectively, these data provide an increased understanding of the biological sequelae of fever, as well as a testable unifying hypothesis, for future antineoplastic treatment strategies.

Introduction

Whole Body Hyperthermia (WBH) is undergoing renewed interest as an adjunct to cytotoxic therapy, (e.g., an international group, the Systemic Hyperthermia Oncological Working Group, has been formed to share technology and protocols) [1]. It is now recognized that when WBH is combined with cytotoxic therapy, it causes increased DNA adduct formation, inhibition of DNA repair, increased drug permeability, as well as decreased resistance to DNA damaging agents [2], [3], [4]. Animal and clinical data support preclinical observations that WBH can enhance cytotoxic ionizing irradiation and chemotherapy (CT) without a commensurate increase in myelosuppression [2], [5], [6], [7], [8], [9], [10]. In this regard, murine studies have demonstrated WBH myeloprotection relative to both chemotherapy [11] and ionizing irradiation [12]. Consistent with these data, are observations of increased peripheral counts in mice [12] after WBH (at a time when count nadirs would be expected, had cytotoxic therapy been given) and dogs [8]. Clinical experience suggests that the use of WBH in the setting of allogenic bone marrow transplantation (BMT) results in early engraftment of donor marrow and enhancement of antineoplastic effects [13]. An explanation for these observations may reside in the induction of cytokines by 41.8°C WBH. The aforementioned investigations have resulted in the formation of a hypothesis: WBH induces a natural balanced cascade of biological events leading to the promotion of growth and differentiation of non-committed progenitor cells. Two corollaries to this hypothesis are: (i) WBH induces peripheral cytokines (especially monokines), which have direct stimulatory effects on hematopoetic tissue. (ii) These peripheral cytokines also stimulate the production of hematopoetic growth factors at the level of the bone marrow (BM). Inherent in the aforementioned proposal is the need for negative feed back loops. Recent data are consistent with this two part hypothesis and are reviewed below.

Section snippets

Cytokine measurements in the peripheral blood

We have demonstrated elevation of granulocyte colony stimulating factor (G-CSF), interleukin (IL)-1, IL-6, IL-8, TNF-α, as well as IL-10 (which should serve as a mediator of negative feedback control [14]) peaking approximately 3 h after completion of WBH (×60 min). We found on average a ∼600% increase over pre-treatment levels of these cytokines [15], [16].

The induction of G-CSF, IL-1β, and IL-6 has a direct stimulatory effect on stem cells and/or progenitor cells related to white blood cell

Bone marrow cytokine induction

Initially, we expected to find WBH induction of GM-CSF and IL-3 in the serum as increased levels of these cytokines would be consistent with our observations regarding WBH myeloprotection and early BM engraftment. However, as described above, increased levels of these cytokines were not observed in the serum of patients during and post WBH. In this regard, some colony stimulating factors appear to act as long-range regulators, that is, G-CSF, IL-6, whereas others appear to act as local acting

Summary and future directions

The aforementioned data taken collectively are consistent with an unifying hypothesis presented in Fig. 2. It provides a basis for the observation that specific anticancer agents (for which myelosuppression is the major toxicity) can have their anti-neoplastic effects markedly enhanced by WBH without a commensurate increase in morbidity [1], [2], [5], [7], [9], [10], [13], [28]. Such observation surely encourages further clinical trials regarding cytotoxic therapy and WBH. Additionally, this

Acknowledgments

This study received the support of: Northwestern Mutual Life Foundation, Inc., Milwaukee, WI, USA; Deutsche Forschungsgemeinschaft, Ka 1169/ 1-1, Wi 1152/ 1-2; Cancer Research Institute, NY, USA.

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