Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration.
OBJECTIVE
A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy.


METHODS
Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein).


RESULTS
After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course.


CONCLUSIONS
It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.
Kleinerman
E S
ES
Department of Cell Biology, University of Texas MD Anderson Cancer Center, Houston 77030.
Jia
S F
SF
Griffin
J
J
Seibel
N L
NL
Benjamin
R S
RS
Jaffe
N
N
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D002097:C-Reactive Protein / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000187:drug effects*; D004337:Drug Carriers; D004341:Drug Evaluation; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D016260:Monocytes, Activated Killer / Q000187:drug effects*; D019798:Neopterin; D012516:Osteosarcoma / Q000188:drug therapy* / Q000276:immunology* / Q000556:secondary; D010714:Phosphatidylethanolamines / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D016207:Cytokines; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; C037144:mifamurtide; D001708:Biopterins; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D019798:Neopterin; D002097:C-Reactive Protein