**5. Conclusion**

*Antisense Therapy*

42, 62, 120, 121].

**4. Discussion**

the vaccine [57, 79].

CD11b+ to CD8+ CD11b− phenotype, an alteration that may reflect the enhanced activation of T cytotoxic cells in blood. Additionally, as far as prognosis of glioblastoma patients is concerned, the patients have survived between 18 and 24 months after the first diagnosis. Generally, patients with diagnosed glioblastoma multiforme, undergoing surgeries and radiotherapy, survive up to 14 months [22, 113]. Our phase I human cancer clinical trial based on the anti-gene, antisense approach, is in progress in the U.S.A, Thailand, Poland and China [107, 114, 115] and is in parallel with previously established approaches of glioblastoma treatment established by either Culver [116] or by Baserga [65]. Following the same approach, different antisense strategies to treat glioma tumors have been recently investigated [26, 31, 117, 118], especially in relation to glycogen metabolism [119] in glioma cells. (Malignant astrocytes present a high level of glycogen [55]). The therapy of gliomas using strategies of growth factors inhibition is in permanent progress. The inhibition of the IGF-I receptor using AS technology, and its signaling pathway has opened a door for experimental and clinical research in various tumors [9, 14, 15,

The use of anti-gene therapy was also effective in another AS approach, targeted toward the molecule, TGF-beta [79]. TGF-beta2 plays a role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. The approach of AS TGF-beta using an AS oligodeoxynucleotide—compound AP 12009, has given satisfactory results [122–124]. AP-12009 treatment was well tolerated and tumor response has been observed [123]. Two patients experienced long-lasting complete tumor remission [124]. In another clinical AS TGF-beta study, a phase I clinical trial in grade IV astrocytoma (GBM) was performed using autologous tumor cells modified by a AS TGF-beta2 vector [79]. There were indications of humoral and cellular immunity induced by

As far as AS TGF-beta therapy of GBM is concerned, the treatment of patients with recurrent or refractory malignant (high-grade) glioma, WHO grade III or IV has been shown to produce results, similar to results obtained with anti IGF-I treatment. The role of peripheral blood mononuclear cells in the immune antitumor response, and prolonged survival in both anti TGF beta and anti IGF-I approaches was comparatively examined. In the case of TGF-beta, it is also important to mention, that although the first successful clinical results were published in 2006–2008, the solid experimental data, using AS technology were obtained in 1994/95 [79], which means, that long periods of research on the mechanism of AS TGF-beta and AS IGF I are required before achieving significant clinical results, confirming the

In AS IGF-I or AS TGF-beta approaches, immune antitumor response, mediated by TCD8 and APC cells, was signaled as a principal mechanism of AS technology inhibiting growth factors and their signaling pathway [12, 79]. These cells being involved in HS (heat shock) protein mechanism, the inhibition of HS was intro-

More recent clinical successful strategies of gliomas treatment, generally as a combination therapy using different types of inhibitors (i.e., imatinib, gefitinib) including antibodies (i.e., avastin) targeting growth factors and their receptors [132–136], are now focusing on anti-gene strategy, especially on antisense or triple helix technologies used alone or combined also with pharmacological treatment. As far as antisense and triple helix strategies are compared, the triple helix blockade of

usefulness of gene therapy in cancer treatment [90, 122, 123, 125–130].

duced in clinical trials as a new direction for cancer therapy [131].

**64**

Among the new strategies in the efforts to successfully treat GBM, the use of AS approach targeting IGF-I, TGF-beta or VEGF, their receptors and their downstream transduction signaling elements [9, 137], appears to offer a promising solution. The final result of the signal transduction pathway element inhibition is an immune response mediated *in vivo* by lymphocytes T CD8 and APC cells. Using cancer immunogene therapy of anti-gene anti IGF-I approach, the median survival of treated glioblastoma patients has reached 22–24 months. But the near future in treating this group of disorders belongs to a combination of treatment: classical surgery, radiotherapy with immunotherapy, pharmacologic therapy, growth factor inhibitors, and the use of the antisense/triple helix gene blockade approach targeting signal transduction pathway elements of cancer processes [16, 22, 23, 36, 66, 90, 125, 138–147].
