Radiolabeled Matrix Metalloproteinase Inhibitors for Breast Cancer Therapy
Abstract
Matrix Metalloproteinases (MMPs), a family of over 20 types of enzymes, collectively are capable of degrading all the components of the extracellular matrix. MMP-2 and MMP-9 (also known as gelatinases) are specifically thought to play critical roles in tumor cell invasion and are frequently co-expressed in breast cancer. Cyclic peptides containing the sequence HWGF have been described as selective inhibitors of MMP-2 and MMP-9. We tested the hypothesis that gelatinase expression may provide a target for in vivo tumor imaging using a radiolabeled gelatinase inhibitor. The peptide, DOTA-CTTHWGFTLC (DOTA-CTT), was labeled with Cu-64 T 1/2 1/2% = l2.7 h.%, which has a decay scheme suitable for both PET imaging and cancer therapy. This conjugate maintained MMP-2 inhibitory activity comparable to %Ilomastat, a broad-range inhibitor of MMPs. An increase in the MMP-2/9 activity of human metastatic breast cancer MDA-MB-435 tumors in nude mice was observed from 4 to 10 weeks post-implantation. MicroPET images of Cu-64-DOTA-CTT in the tumor-bearing nude mice showed tumor uptake at 8-wk post-implantation; however, the same mouse with 5-wk palpable tumors showed no uptake of the tracer, suggesting that the MMP-2 and MMP-9 activity is related to the stage of tumor growth. These data suggest the potential of radiolabeled gelatinase inhibitors as markers for imaging the metastatic capability of human breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2002
- Accession Number
- ADA410082
Entities
People
- Caroyln J. Anderson
Organizations
- Washington University in St. Louis