ABSTRACT
MMP inhibitors (MMPIs) have mostly been developed to treat cancer by suppressing tumor growth, and they have been evaluated over a wide
range of animal models and in vivo pharmacological experiments. One initial challenge was poor oral bioavailability, which led to a higher inhibitor dosage requirement, and secondly, targeting issues abound as MMPs also share similar structure at active sites, making their inhibitors non-selective. This limitation has further complicated the ability to achieve adequate inhibitory concentrations. Hydroxamate, a chelating agent that binds Zn2+ ion inhibiting MMP activity (Jani et al. 2005), has been shown to increase metastasis in certain animal models (Deryugina and Quigley 2006). Lung metastasis was not significantly reduced when treated with batimastat, a metalloproteinase inhibitor, in immunodeficient mice injected with human carcinoma cells. Of note, batimastat induced liver metastasis, and unusual occurrence (Deryugina and Quigley 2006). Clinical trials involving MMPIs failed in the late 1990s due to broad inhibition of other MMPs causing severe musculoskeletal diseases (Turk 2006; Palermo and Joyce 2008). Interestingly, negative correlations between MMP expression and cancer progression have also been observed in several cancers such as pancreatic, colorectal, breast, cervical, and melanoma (Mook et al. 2004; Garcea et al. 2005; Hofmann et al. 2005; Deryugina and Quigley 2006). Just as with cathepsins, it appears that turning MMPs off can elicit as many side effects as their upregulation indicating the important balance of their activity in healthy and disease environments.
