Enhanced anti-metastatic efficacy of IL-2 activated NK (A-NK) cells with novel benzothiazoles.
We have previously shown that A-NK cells when locoregionally administered accumulate within established cancer metastases and establish direct contact with both tumor cells and microvascular endothelial cells. Nevertheless, the accumulation of adoptively transferred A-NK cells into established cancer metastases is not sufficient for therapeutic efficacy in the B16 melanoma model. We have therefore attempted to enhance the anti-metastatic therapeutic efficacy of adoptively transferred A-NK cells with standard anticancer chemotherapeutic agents. We have found that chemoimmunotherapy with A-NK cells plus cyclophosphamide to be more effective than A-NK cell adoptive immunotherapy alone. We have now built on these findings, by examining the ability of novel biologic response modifiers (low molecular weight benzothiazole compounds) to augment adoptive immunotherapy with A-NK cells. Two compounds KB-R4107 (4-methoxy-2-(4-t-butylphenyl)benzothiazole) and KB-R4250 (4-methoxy-2-(4-trifluoromethylphenyl)benzothiazole) enhanced reduction of B16 melanoma pulmonary metastases mediated by A-NK cell adoptive immunotherapy. Both compounds were administered for 5 days prior to administration of A-NK cells at 100 mg/kg p.o. All experimental groups initially contained at least 7 animals and were examined for tumor burden on day 10. With B16 melanoma cells administered on day 0 and A-NK cells administered on Day 4, KB-R4107 and KB-R4250 yielded on average a 64% and 52% reduction in metastatic burden, respectively compared to an average 17% reduction using A-NK cells alone. In contrast these compounds did not diminish metastatic burden when administered alone. KB-R4107 and KB-R4250 are therefore low molecular weight, heterocyclic, biological response modifiers which can augment the anti-metastatic therapeutic effect of adoptively transferred A-NK cells.
Goldfarb
R H
RH
University of Pittsburgh Cancer Institute, PA, USA. rgoldfar@hsc.unt.edu
Kitson
R P
RP
Brunson
K W
KW
Yoshino
K
K
Hirota
N
N
Kirii
Y
Y
Kotera
Y
Y
Inoue
Y
Y
Ohashi
M
M
D000818:Animals; D052160:Benzothiazoles; D004354:Drug Screening Assays, Antitumor; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
C121191:4-methoxy-2-(4-t-butylphenyl)benzothiazole; C121192:4-methoxy-2-(4-trifluoromethylphenyl)benzothiazole; D052160:Benzothiazoles; D007155:Immunologic Factors; D007376:Interleukin-2; D013844:Thiazoles