Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases.
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.
Quintieri
L
L
Department of Oncology and Surgical Sciences, University of Padova, Italy.
Rosato
A
A
Amboldi
N
N
Vizler
C
C
Ballinari
D
D
Zanovello
P
P
Collavo
D
D
D000293:Adolescent; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D000922:Immunotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007376:Interleukin-2; D015979:Killer Cells, Lymphokine-Activated; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000628:therapy*; D051379:Mice; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000922:Immunotoxins; D007376:Interleukin-2; C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin