These subtle but highly orchestrated neurovascular and gliovascular immune

Bcl 2 targeting and chemoradiotherapy induced elimination of A375 melanoma is not due to immune stimulation Immune stimulation has been observed with CpG con taining antisense oligonucleotides. Previous studies have shown nonantisense effects, such as production 価格 INNO-406 of reactive oxygen species and immunostimulatory action, elicited by bcl 2 antisense oligodeoxynucleotides through cytosine phosphate guanosine motifs. For instance, CpG oligonucleotides may enhance the tumor response to radiotherapy. Theoretically all phosphorothioate oligos, even those that do not contain CpG motifs, will bind to TLR 9, are hence immunostimulatory to some extent, and should increase levels of circulating cytokines.<br><br> In particular, CpG oligonucleotides administered in single peritumoral sub cutaneous injections three times per week resulted in ele vated plasma levels of IL 12 and significant inhibition of the growth of melanoma xenografts by approx. 60% com pared to the Lapatinib 臨床試験 saline control. Therefore it is a matter of discussion which property is the main responsible of the antitumor effects. Is the melanoma shrinkage due to the down regulation of Bcl 2 and resulting chemosensiti zationOr is it due predominately to increased cytokine activity with Bcl 2 playing a lesser role in vivoTo answer this important question we measured leukocyte and cytokine levels in circulating blood and serum, respec tively. We focused on the treatment conditions that led to complete melanoma regression in vivo. As shown in Table 2 the combination of G3139 VRP ACV PAC.<br><br> PBP DNR X rays causes a profound leu copenia with lower levels of all white cell subtypes as compared to controls. Serum cytokine levels were lower in A375 melanoma bearing Lonafarnib ic50 mice trea ted with G3139 VRP ACV PAC. PBP DNR X rays than in controls treated with physiological saline. Thus it appears obvious that, in our therapeu tic strategy, melanoma regression is not due to immune stimulation. In fact, immune stimulation by CpG motifs and antitumor effects in SCID mice could be indepen dent effects. As shown in Table 1 it should be noted that G3139 administration does not affect melanoma growth. and that G3139 chemotherapy PAC. PBP DNR only decreases melanoma growth by approx. 50%. Therefore, as suggested by the data in Table 1 the use of G3139, as a single agent or com bined with chemotherapy, may render only limited effects against advanced melanoma.<br><br> Discussion The inability of undergo apoptosis in response to che motherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Recently numerous cellular pathways important to melanoma cell proliferation, apoptosis, or metastases have been shown to be activated. Activation occurs through specific mutations or changes in proteins expression. Thus, it is generally assumed that multi target directed therapies will be needed to produce significant clinical benefits in patients. In particular, bcl 2 overexpression in different human melanoma cells appears to favour tumor progression associated properties and in vivo growth, thus mak ing Bcl 2 a rational target for anticancer therapy.