**1.6 Vincristine**

588 Pharmacology

cytokine produced cell. Cytokine binds to a specific receptor and causes a change in function or in development (differentiation) of the target cell. In both cases, i.e. autocrine and paracrine regulation mechanisms the expression of the membrane receptor is altered. **1.3.1 Interleukins a**re a group of cytokines which are produced by a wide variety of body cells. The majority of interleukins are synthesized by helper CD4+ T lymphocytes, monocytes/macrophages and by endothelial cells. If the produced cytokine is released, then it is measurable in the supernatant, if not then the cytokine is measurable only intracellular. **Interleukin-6 (**IL-6) originally defined as a B cell differentiation factor is produced by different cell types and certain tumour cells. Interleukin-6 acts as a pro-inflammatory and an anti-inflammatory cytokine. As a pro-inflammatory cytokine regulates inflammatory reactions either directly or indirectly. As an anti-inflammatory cytokine Interleukin-6 reduces the inflammatory reactions. IL-6 exits in three molecular weights, i.e. 21-30 kDa, 150-200 or 450 kDa. The biological activity of IL-6 depends on binding to its specific receptors. These membrane receptors composed the glycoprotein gp80 Interleukin-6 receptor alpha (IL-6R, also called CD126) and a signal-transducing component gp130 (also called CD 130). The complex IL-6+IL-6R+gp130 initiate a signal transduction cascade through JAKs (Janus kinases) and STATs (Signal Transducer-Activator of Transcription). The membrane receptors are released from the cells as soluble receptor proteins (sIL-6R and sgp130). As agonist, sIL-6R enhances the biological activity of IL-6 and sgp130 is an

Interleukin-6 is a major proliferative factor for the malignant plasma cells (multiple myeloma cells). This cytokine produces by the plasma cells and it affects the cells by an autocrine regulation mechanism with an additional paracrine signalling. IL-6 in a

The multiple myeloma cells can be classified into three groups depending on exogenous IL-6: (a) both proliferation and survival of the cells are dependent on IL-6, (b) only proliferation of the myeloma cells is affected by IL-6, (c) the cells are dependent on IL-6 only for survival, but not for proliferation. However there are also some cell lines that are independent of IL-6 both for survival and proliferation. The serum values of IL-6 in 35% or in 97% or in 42% of multiple myeloma patients were significantly higher than in healthy persons (Nachbour et

Because about 70% of the secreted IL-6 forms a complex with sIL-6R (Gaillard et al., 1987), the amount of the free IL-6 in serum is low. Therefore the serum level of the sIL-6R is an important parameter in the evaluation and in the progression of multiple myeloma

**Interleukin-10** (IL-10) is known as a human cytokine synthesis inhibitory factor (CSIF). It produces by Thelper2 cells, monocytes/macrophages, by B lymphocytes and some tumour cells. Interleukin-10 has (1) immunosuppressive effect and (2) immunostimulatory effect. It down-regulates the expression of Thelper1 cytokines, MHC class II antigens and costimulatory molecules on macrophages. Interleukin-10 is a pleiotropic cytokine which increases Bcl-2 levels and protects cells from steroid or doxorubicin-induced apoptosis.

How might the presence of IL-10 contribute to a poor prognosis for some cancer? One possibility: Interleukin-10 is a growth factor for tumour cells. Second possibility: Interleukin-

concentration of 2pg/ml can induce 50% proliferation in myeloma cells.

al., 1991; DuVillard et al., 1995; Wierzbowska et al., 1999).

(Papadaki et al., 1997; Wierzbowska et al., 1999).

10 suppresses the anti-tumour immune responses.

antagonist against the complex IL-6+sIL-6R.

Vincristine is a vinca alkaloid. As a chemotherapeutic agent is used mainly in combination with other chemotherapeutic substances in the therapy of multiple myeloma. Vincristine inhibits the proliferation of these tumour cells and as a CCS blocker (El Alaoui, 1997; Lin et al., 1998; Mastberger et al., 2000) arrests the cell cycle phase G2/M by blocking the mitotic spindle formation (Harmsma et al., 2004).
