Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide.
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-1 beta 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 pre-therapy 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.
Landmann
R
R
Department of Research, University Hospital, Basle, Switzerland.
Obrist
R
R
Denz
H
H
Ludwig
C
C
Frost
H
H
Wesp
M
M
Rordorf
C
C
Towbin
H
H
Gygax
D
D
Tarcsay
L
L
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy; D007958:Leukocyte Count / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D019798:Neopterin; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D016207:Cytokines; D008081:Liposomes; D010714:Phosphatidylethanolamines; C037144:mifamurtide; D001708:Biopterins; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019798:Neopterin