Adoptive transfer of lymphokine-activated killer cells loaded with 4'-deoxy-4'-iododoxorubicin: therapeutic effect in mice bearing lung metastases.
We studied the potential use of lymphokine-activated killer (LAK) cells loaded with 4'-deoxy-4'-iododoxorubicin (IDX) in adoptive immunotherapy experiments. Because LAK cells preferentially locate in the lung, we evaluated the therapeutic effect of IDX-loaded LAK cells in mice bearing lung metastases induced by B16F1 tumor cell injection. In vitro studies showed that LAK cells rapidly incorporated IDX, with maximum uptake at 15 min, followed by a plateau; drug efflux was initially rapid and then continued at a much slower rate. Evaluation of LAK cell cytotoxic activity against relevant target cells showed a 30% decrease after IDX treatment that progressed with time over the next 6 h. P388 tumor cell growth was inhibited by coculture with IDX-loaded LAK cells, thus demonstrating that the released IDX maintained its pharmacological activity. Finally, high performance liquid chromatography analysis of tissue IDX concentration revealed a considerably higher and long-lasting concentration in the lungs of mice receiving IDX-loaded LAK cells, compared to mice given injections of a comparable amount of free drug. Moreover, adoptive transfer of IDX-loaded LAK cells into tumor-bearing mice caused a significant reduction in the number of lung metastases versus control mice given injections of even higher doses of free drug.
Mandruzzato
S
S
Institute of Oncology, University of Padua, Italy.
Rosato
A
A
Bronte
V
V
Zanovello
P
P
Amboldi
N
N
Ballinari
D
D
Collavo
D
D
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA
C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin