Anti-metastatic treatments

Nevertheless, proteinase inhibitors may therefore be useful as therapeutic agents in anti-invasive and anti-metastatic treatment. Studies have shown that potato cysteine proteinase inhibitor PCPI 8.7 inhibited invasion B16 mouse melanoma cell by 21% and serine proteinase inhibitor reduced invasiveness by up to 24 % (Sever et al., 2005). Overexpression of cathepsin B excessively associated with adenocarcinoma of the esophagus and other cancers (Kos Lah, 1998). 

Tamamura H, Hori A, Kanzaki N, et al. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett 2003 550 79-83. 

The peptide CXCR4 antagonist TN14003 has demonstrated antitumor efficacy in two animal models of metastatic breast and head and neck cancer [48, 103]. Animals were treated with the CXCR4 peptide by intraperitoneal injection for 35 days. Tumors at the primary subcutaneous site of injection as well as the number of lung metastasis were inhibited. In the head and neck animal model, antitumor activity was correlated with anti-angiogenic activity of the anti-CXCR4 treatment. 

Tamamura, H., Hori, A., Kanzaki, N., Hiramatsu, K., Mizumoto, M., Nakashima, H., Yamamoto, N., Otaka, A., and Fujii, N. (2003) T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Letters, 550, 79-83. 

ADCC. Cetuximab is approved for treatment of metastatic colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN). Interestingly, an adverse event, acneiform rash seems to correlate with a better response to cetuximab, while there is no such correlation with expression levels of EGFR assessed by immunohistochemistry. Further side effects are rare infusion reactions and hypomagnesia. Two other anti-EGFR antibodies approved for clinical use are the fully human antibody panitumumab (Vectibix)... 

Umemura, S., Sekido, Y., Itoh, H., and Osamura, RY. 2002. Pathological evaluation of HER2 overexpression for the treatment of metastatic breast cancers by humanized anti-HER2 monoclonal antibody (trastuzumab). Acta Histochemica et Cytochemica, Kyoto 35(2), 77-81. 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

While no in vivo activity has been reported in an Abl-dependent CML model, AZD0530 was active in a xenograft model using Src-transformed NIH 3T3 cells and in an orthotopic model of pancreatic cancer, two Src-dependent models. The results of a Phase I trial in normal volunteers have been disclosed and AZD0530 was tolerated when administered at doses of up to 250 mg [156,157]. While it appears that the initial efficacy trial for AZD0530 will be as an anti-invasive agent for the treatment of metastatic bone disease, this compound probably also has potential for use in CML. 

Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-pl 85HER2/neu monoclonal antibody plus cisplatin in patients with HER2/ neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998 16 2659-2671. 

In another study involving patients with metastatic breast, colorectal and ovarian cancer, increased anti-sTn titers were correlated with better survival. Even if before treatment, elevated titers of antibodies against the mucin MUC1, were correlated with a poor response to immunotherapy, CTL precursors to the MUC1 were detected in carcinoma patients [208], A vaccine using 10 pg/ml MUC1-KLH mixed with Detox was injected s.c. in breast cancer patients treated with cyclophosphamide. A weak antibody response, and an ex vivo CTL response against HLA-matched adenocarcinoma cell lines were seen. No correlation with the clinical outcome was available [209],... 

The results of these preclinical tumor studies revealed that distant primary and metastatic tumors may be treated by i.m. injection of a therapeutic pDNA. This type of anti-cancer therapy could be useful for the treatment of human neoplasms. One advantage of this type of therapy is that tumors in organs that are difficult to access may be treated by a simple i.m. injection. The therapy may also prevent the growth and spread of metastases. 

Vogel, C. L., Cobleigh, M. A., Tripathy, D., Harris, L., Fehrenbacher, L., Slamon, D., Ash, M., Novotny, W., and Shak, S. (1998). Efficacy and safety of Herceptin (Trastuzumab, humanized anti-HER-2 antibody) as a single agent in first-line treatment of HER-2 overexpressing metastatic breast cancer (HER-2+/MBC). Breast Cancer Res. Treat. 50, 232a. 

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