TY - JOUR
T1 - Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells
T2 - Effect in mice bearing hepatic metastases
AU - Quintieri, L.
AU - Rosato, A.
AU - Amboldi, N.
AU - Vizler, C.
AU - Ballinari, D.
AU - Zanovello, P.
AU - Collavo, D.
PY - 1999
Y1 - 1999
N2 - 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 μg kg-1 MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 μg 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.
AB - 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 μg kg-1 MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 μg 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.
KW - A-NK cell
KW - Drug delivery
KW - Liver metastases
KW - Methoxymorpholinyl doxorubicin
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U2 - 10.1038/sj.bjc.6690171
DO - 10.1038/sj.bjc.6690171
M3 - Article
C2 - 10098738
AN - SCOPUS:0032982751
VL - 79
SP - 1067
EP - 1073
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 7-8
ER -