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.

• Authors: R H Goldfarb, R P Kitson, K W Brunson, K Yoshino, N Hirota, Y Kirii, Y Kotera, Y Inoue, M Ohashi
• Journal: Anticancer research (Anticancer Res) 1999 May-Jun Vol. 19 Issue 3A Pg. 1663-7 ISSN: 0250-7005 [Print] Greece
• PMID: 10470098 (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)