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Enhanced anti-metastatic efficacy of IL-2 activated NK (A-NK) cells with novel benzothiazoles.

Abstract
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.
AuthorsR H Goldfarb, R P Kitson, K W Brunson, K Yoshino, N Hirota, Y Kirii, Y Kotera, Y Inoue, M Ohashi
JournalAnticancer research (Anticancer Res) 1999 May-Jun Vol. 19 Issue 3A Pg. 1663-7 ISSN: 0250-7005 [Print] GREECE
PMID10470098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-methoxy-2-(4-t-butylphenyl)benzothiazole
  • 4-methoxy-2-(4-trifluoromethylphenyl)benzothiazole
  • Benzothiazoles
  • Immunologic Factors
  • Interleukin-2
  • Thiazoles
Topics
  • Animals
  • Benzothiazoles
  • Drug Screening Assays, Antitumor
  • Immunologic Factors (pharmacology, therapeutic use)
  • Immunotherapy, Adoptive
  • Interleukin-2 (pharmacology)
  • Kidney (pathology)
  • Killer Cells, Natural (drug effects, immunology)
  • Liver (pathology)
  • Liver Neoplasms (prevention & control, secondary)
  • Lung (pathology)
  • Lung Neoplasms (prevention & control, secondary)
  • Melanoma, Experimental (prevention & control, secondary)
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Neoplasm Metastasis (prevention & control)
  • Neoplasm Transplantation
  • Organ Size (drug effects)
  • Specific Pathogen-Free Organisms
  • Thiazoles (chemistry, pharmacology, therapeutic use)

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