Abstract
The DNA enzyme Dz13, targeted against the oncogene c-Jun, is capable of inhibiting various model tumours in mice albeit in ectopic models of neoplasia. In previous studies using orthotopic models of disease, the inhibitory effects of Dz13 on secondary growth was a direct result of growth inhibition at the primary lesion site. Thus, the direct and genuine effects on metastasis were not gauged. In this study, Dz13 was able to inhibit both locoregional and distal metastasis of tumour cells in mice, in studies where the primary tumours were unaffected due to the late and clinically-mimicking nature of treatment commencement. In addition, the effect of Dz13 against tumours has now been extended to encompass breast and prostate cancer. Dz13 upregulated the matrix metalloproteinase (MMP)-2 and MMP-9, and decreased expression of MT1-MMP (MMP-14) in cultured tumour cells. However, in sections of ectopic tumours treated with Dz13, both MMP-2 and MMP-9 were downregulated. Thus, not only is Dz13 able to inhibit tumour growth at the primary site, but also able to decrease the ability of neoplastic cells to metastasise. These findings further highlight the growing potential of Dz13 as an antineoplastic agent.
Highlights
Dz13 is a DNA enzyme designed originally to reduce intimal thickening in injured rat carotid arteries [1]
Dz13 has been shown in ectopic mouse tumour models to reduce the growth of melanoma indirectly via antiangiogenesis [3], while exhibiting direct activity against squamous cell carcinoma [4], osteosarcoma, OS [5,6] and
And distally metastasising osteosarcoma model In this study, when 143B cells were injected into the fatpad, palpable tumours arose at 3 weeks post-injection
Summary
Dz13 is a DNA enzyme designed originally to reduce intimal thickening in injured rat carotid arteries [1]. Since this particular 'gene shear' molecule has been shown to have potential therapeutic effects against a variety of disorders as mentioned below. DNAzymes are synthetic, single-stranded DNA-based catalysts engineered to bind to their complementary sequence in a target messenger RNA (mRNA) through Watson-Crick rules for base-pairing and cleave the mRNA at predetermined phosphodiester linkages (reviewed in [2]). Dz13 cleaves the target human c-Jun mRNA at position G1311[1]. By way of a handful of critical studies, these biocatalytic molecules have emerged as a potential new class of nucleic acid-based drugs because of several beneficial attributes [2]. Dz13 has been shown in ectopic mouse tumour models to reduce the growth of melanoma indirectly via antiangiogenesis [3], while exhibiting direct activity against squamous cell carcinoma [4], osteosarcoma, OS [5,6] and
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