Abstract
Prostate secretory protein 94 (PSP-94) has been shown to exert anti-tumor activity against prostate cancer cells, particularly in the form of PCK3145, a synthetic peptide corresponding to amino acids 31–45 of PSP-94. Indeed, when tested in a murine model, this peptide could reduce experimental prostate tumour growth. In addition, when evaluated in a Phase I clinical study, this peptide demonstrated a particularly interesting safety profile, with almost complete lack of toxicity. In order to determine whether PCK3145 could exert cytotoxic activity against other marrow infiltrating cancers, we tested its activity both in vitro and in vivo against non-Hodgkin’s lymphoma (NHL) and other hematologic cancers. Interestingly, PCK3145 inhibited the proliferation of human NHL (SR) and myeloma (RPMI-8226) cell lines in vitro. To explore its anti-tumor activity in vivo, the impact of PCK3145 was also measured by inoculating P815 malignant cells into syngeneic DBA mice. First, four groups of 6 DBA mice were injected subcutaneously with 2x104 P815 cells and then treated with subcutaneous injections of PCK3145, and compared to
a peptide with the scrambled amino acid sequence, PCK5266 (peptide derived from amino acids 52 to 66 of PSP-94), and phosphate-buffered saline (PBS).
Treatment with PCK3145 significantly decreased the growth of P815 tumours in comparison to PBS (p<0.001), scrambled peptide (p<0.05) and PCK5266 (p<0.01), confirming in vivo anti-tumor activity and suggesting that tumour growth inhibition is due to the specific amino acid sequence of PCK3145. The same model was used to determine the effect of PCK3145 on metastatic dissemination following intraperitoneal administration of the peptide. PCK3145 treatment led to a decreased number of liver metastasis compared to PBS (p<0.05) and scrambled peptide (p<0.05) controls. In order to determine whether PCK3145 exerted its activity by altering metalloproteinase release, metalloproteinase MMP-9 levels were measured 3 weeks post-tumor cell exposure. MMP-9 levels, measured by ELISA, in the peripheral blood of treated P815 bearing mice were similar to those obtained with healthy animals (12.83±1.890 (mean±SD) ng/ml and 7.183±0.4070 ng/ml, respectively), while MMP-9 levels were elevated in mice treated with PBS and scrambled peptide (35.12±8.559 ng/ml and 22.60±3.944 ng/ml, respectively; p<0.05). We next tested PCK3145 treatment on human SR lymphoma cell line grown subcutaneously in NOD/SCID mice. Similarly to results obtained with murine tumors, treatment with PKC3145 resulted in significant inhibition of SR non-Hodgkin’s lymphoma growth compared to treatment with PBS (p<0.001) and scrambled peptide (p<0.01). These results demonstrate that in vivo treatment with PCK3145 can reduce tumor cell proliferation of both murine and human hematologic cancers. In addition, PCK3145 has the potential to inhibit tumor cells dissemination by lowering MMP-9 secretion. Thus, PCK3145 represents a unique peptide demonstrating sequence-specific anti-tumor activity against NHL and other hematologic malignancies. Based on these results, clinical studies are being designed to evaluate its therapeutic activity in humans.
HYAL1 and HYAL2 Inhibit Tumour Growth In Vivo but Not In Vitro
