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Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide

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Biotherapy

Abstract

The macrophage activator muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) was infused in liposomal form in 14 metastatic cancer patients (4 mg i.v. during 30 min twice weekly for 12 weeks). Clinical, pharmacokinetic and immunological parameters were studied before and 0.5, 2, 4, 24 and 72h after start of drug infusion in week 1, 4, 8 and 12. No tumor regressions were seen. Tumors progressed in 11 patients, in 4 of them within 2 months; 3 patients had stable disease. The intensity and frequency of side effects (fever and nausea) diminished from week 1 to 12. The rate of disappearance of total and free MTP-PE from blood was rapid and mean serum concentration-time curves remained unchanged throughout 12 study weeks. MTP-PE caused a marked increase of serum TNFa, IL-1 receptor antagonist (IL-1ra) and IL-6 in week 1, but not thereafter. In contrast, MTP-PE caused a persistent, 2-fold increase in serum neopterin and young forms of granulocytes (bands) during week 1 to 12. Before therapy, monocyte tumor cytotoxicity and in-vitro monocyte derived TNFa, IL-1Β and IL-6 production were low in 9 patients (group L, <15%) and high in 5 patients (group H, >40%). Monocyte cytotoxicity and in-vitro cytokine production was transiently enhanced in week 1 in group L, it declined under therapy in group H. In conclusion, MTP-PE induced marked initial immunomodulation; the extent of the ex vivo monocyte cytokine and tumor cytotoxic response was dependent on pretherapy cell activity. A decrease of the cytokine and IL-1ra response during prolonged therapy contrasted with a persistent increase of neopterin and juvenile blood granulocytes. The long lasting biologic effects may be relevant to direct future clinical studies with liposomal MTP-PE in an adjuvant setting.

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Abbreviations

MTP-PE:

muramyl tripeptide-phosphatidyl ethanolamine

IL-1ra:

IL1 receptor antagonist

TNFa:

tumor necrosis factor alpha

IL-1Β :

interleukin-1 beta

IL-6:

interleukin 6

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Author notes

  1. Regine Landmann

    Present address: Department of Research and Internal Medicine, Division of Oncology, University Hospital, Switzerland

Authors and Affiliations

  1. Department of Research and Internal Medicine, Division of Oncology, University Hospital, Switzerland

    Reto Obrist, Hubert Denz, Christian Ludwig & Jean -Paul Obrecht

  2. Department of Pharma Division, Ciba-Geigy Ltd., Basle, Switzerland

    Heiner Frost, Martin Wesp, Christine Rordorf, Harry Towbin, Daniel Gygax & Lajos Tarcsay

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  1. Regine Landmann
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  2. Reto Obrist
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  4. Christian Ludwig
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  7. Christine Rordorf
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Landmann, R., Obrist, R., Denz, H. et al. Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide. Biotherapy 7, 1–12 (1993). https://doi.org/10.1007/BF01878149

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  • DOI: https://doi.org/10.1007/BF01878149

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