Colorectal cancer is one of the commonest malignant tumors and has a relatively poor prognosis. The outcome depends on the extent of local and particularly metastatic tumor spread. The matrix metalloproteinases (MMPs) are a family of closely related enzymes that degrade the extracellular matrix and are considered to be important in facilitating tumor invasion and spread (1-3). Using immunohistochemistry we have investigated the occurrence in colorectal cancer of MMP-1 (interstitial collagenase). Our monoclonal antibody was prepared against a synthetic peptide corresponding to an amino acid sequence specific for MMP-1 and was selected to react in formalin-fixed wax-embedded sections, thus allowing use in diagnostic histopathology and also enabling access to archival material. We found that the presence of MMP-1 in colorectal cancer is associated with a poor prognosis (P = 0.006) and has prognostic value independent of Dukes stage. One MMP inhibitor that strongly inhibits MMP-1 has already been shown to inhibit growth of human colon cancer xenografts in nude mice (4). Our results suggest that treatment of those individuals whose colon tumors produce MMP-1 with MMP inhibitors is a therapeutic strategy worth pursuing.

All strains of Neisseria gonorrhoeae with reduced susceptibility to ceftriaxone and cefixime (cephalosporinintermediate-resistant [Ceph i ] strains) contain a mosaic penA allele encoding penicillin-binding protein 2 (PBP 2) with nearly 60 amino acid differences compared to the sequence of wild-type PBP 2, together with a set of resistance determinants (i.e., mtrR, penB, and/or ponA1) that are required for high-level penicillin resistance. To define the individual contributions of these determinants to reduced susceptibility to ceftriaxone and cefixime, we created isogenic strains containing the mosaic penA allele from the Ceph i strain 35/02 (penA35) together with one or more of the other resistance determinants and determined the MICs of penicillin G, ceftriaxone, and cefixime. The majority of cefixime resistance is conferred by the penA35 allele, with only a small contribution coming from mtrR and penB, whereas ceftriaxone resistance is nearly equally dependent upon mtrR and penB. Unlike high-level penicillin resistance, the ponA1 allele does not appear to be important for Ceph i . A strain containing all four determinants has increased resistance to ceftriaxone and cefixime but not to the levels that the donor Ceph i strain does, suggesting that Ceph i strains, similar to high-level-penicillinresistant strains, contain an additional unknown determinant that is required to reach donor levels of resistance. Our data also suggest that the original Ceph i strains arose from the transformation of penA genes from commensal Neisseria species into a penicillin-resistant strain already harboring mtrR, penB, ponA1, and the unknown gene(s) involved in high-level penicillin resistance.

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Background-The matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are strongly implicated in tumour invasion and metastasis. Aims-To investigate the presence of individual MMPs and TIMPs in gastric cancer. Methods-The presence of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 was identified in a group of gastric cancers (n=74) by immunohistochemistry using monoclonal antibodies. These antibodies were eVective on formalin fixed, paraYn wax embedded sections. Results-A large proportion (94%) of gastric cancers contained MMP-2; MMP-1 and MMP-9 were also detected in 73% and 70% of tumours respectively. MMP-3 was only present in 27% of tumours. MMP-1 and MMP-9 were found predominantly in intestinal type tumours. TIMP-1 and TIMP-2 were identified in 41% and 57% of tumours respectively. Immunoreactivity for individual MMPs or TIMPs was not identified in normal stomach. Conclusions-This study shows the presence of matrix metalloproteinases, particularly MMP-2, and TIMPs in stomach cancer. Antibodies which are eVective in formalin fixed, paraYn wax embedded sections are useful for the identification of MMPs and TIMPs in diagnostic specimens. (Gut 1998;43:791-797)

Colorectal cancer is one of the commonest malignant tumors and has a relatively poor prognosis. The outcome depends on the extent of local and particularly metastatic tumor spread. The matrix metalloproteinases (MMPs) are a family of closely related enzymes that degrade the extracellular matrix and are considered to be important in facilitating tumor invasion and spread (1-3). Using immunohistochemistry we have investigated the occurrence in colorectal cancer of MMP-1 (interstitial collagenase). Our monoclonal antibody was prepared against a synthetic peptide corresponding to an amino acid sequence specific for MMP-1 and was selected to react in formalin-fixed wax-embedded sections, thus allowing use in diagnostic histopathology and also enabling access to archival material. We found that the presence of MMP-1 in colorectal cancer is associated with a poor prognosis (P = 0.006) and has prognostic value independent of Dukes stage. One MMP inhibitor that strongly inhibits MMP-1 has already been shown to inhibit growth of human colon cancer xenografts in nude mice (4). Our results suggest that treatment of those individuals whose colon tumors produce MMP-1 with MMP inhibitors is a therapeutic strategy worth pursuing.