Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

• Published in: British journal of cancer Vol. 79; no. 7-8; pp. 1067 - 1073
• Main Authors: QUINTIERI, L, ROSATO, A, AMBOLDI, N, VIZLER, C, BALLINARI, D, ZANOVELLO, P, COLLAVO, D
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.03.1999
• Subjects: Adolescent; Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Humans; Immunotherapy, Adoptive - methods; Immunotoxins - administration & dosage; Immunotoxins - pharmacokinetics; Interleukin-2; Killer Cells, Lymphokine-Activated; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Lymphoma, Large B-Cell, Diffuse - therapy; Medical sciences; Mice; Pharmacology. Drug treatments; Regular; Tumor Cells, Cultured; Antineoplastic agent; Encapsulation; Animal model; Liver; Hepatic disease; Metastasis; Morpholine derivatives; Doxorubicin; Lipophilic compound; Interleukin 2; Established cell line; Delivery system; Cytokine; Rodentia; Malignant tumor; Natural killer cell; Vertebrata; Antibiotic; Chemotherapy; Mammalia; Treatment; Mouse; Analog; Animal; Digestive diseases; Anthracyclins
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6690171

The possibility of using interleukin 2 (IL-2)-activated natural killer cells (A-NK) to carry methoxymorpholinyl doxorubicin (MMDX; PNU 152243) to liver-infiltrating tumours was explored in mice bearing 2-day established M5076 reticulum cell sarcoma hepatic metastases. In vitro, MMDX was 5.5-fold more potent than doxorubicin against M5076 tumour cells. MMDX uptake by A-NK cells correlated linearly with drug concentration in the incubation medium [correlation coefficient (r) = 0.999]; furthermore, as MMDX incorporation was readily reproducible in different experiments, the amount of drug delivered by A-NK cells could be modulated. In vivo experiments showed that intravenous (i.v.) injection of MMDX-loaded A-NK cells exerted a greater therapeutic effect than equivalent or even higher doses of free drug. The increase in lifespan (ILS) following A-NK cell delivery of 53 microg kg(-1) MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 microg kg(-1) free drug, a dosage close to the 10% lethal dose (ILS 42% vs. 38% respectively). These results correlated with pharmacokinetic studies showing that MMDX encapsulation in A-NK cells strongly modifies its organ distribution and targets it to tissues in which IL-2 activated lymphocytes are preferentially entrapped after i.v. injection.