Differentiating agents, effects tumor cells

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

The control of cell numbers is regulated by cell proliferation, differentiation and apoptosis. Increased proliferation and/or decreased apoptosis result in neoplasia. In addition to inhibition of proliferation or induction of differentiation, the modulation of apoptosis can be employed for treatment for cancer. Several anticancer agents in use are potent inducers of apoptosis (Dive and Hickman, 1991 Fisher, 1994). Tumor promotion may result in decreased apoptosis. Because PKC activation by TPA induces carcinogenesis, it seems that PKC may be involved in apoptosis. There are many reports on the effects of PKC on apoptosis. However, the results are very controversial. Here an overview of these data is presented. 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

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