Exploiting changes in the tumour microenvironment with sequential cytokineand matrix metalloprotease inhibitor treatment in a murine breast cancer model

The study of treatment-induced changes in the tumour microenvironment might lead to effective combinations of biological therapy. IL-12 induced tumour regression and cure of an experimental murine breast cancer, HTH-K, but on ly after long-term treatment that was associated with chronic toxicity. Dur ing IL-12 therapy, tumour levels of the matrix metalloprotease MMP-9 declin ed and its inhibitor TIMP-1 was strongly induced. We therefore administered alternate cycles of IL-12 and the MMP inhibitor Batimastat (BB94) to mice. Therapeutic efficacy was increased compared with short-term IL-12 therapy but without the chronic toxicity associated with long-term IL-12 treatment. Image analysis of treated tumours revealed that BB94 prevented regeneratio n of tumour and stromal compartments that normally occurred after short-ter m IL-12 therapy. (C) 2000 Cancer Research Campaign http://www.bjcancer.com.