Tumor modulators

In a study by Stresser and co-workers, the effect on tumor modulation by 227 has been investigated. HPLC on liver extracts from Fisher 344 rats revealed two major compounds, 3,3 -bisindolylmefliane (133) and a linear trimer, together with a < l(KX)-fold lower content of 4 in comparison with the two major substances. The HPLC isolate was derivatized with /V-methyl-/V-bis(trifluoroacetamide) that, upon MS detection, gave a compound identical to /V,W -ditrifluoroacetylindolo-[3,2-()]carbazole. The content of 4 in this system was estimated to be 0.(XKX)13% of the total dose of 227 given. Thus, it was concluded that the beneficial effect of oral distribution of 227 is due to the total content of derivatives formed (95MI5). 

Trout, therefore, respond to a wide variety of tumor-modulating compounds and, as a result, can offer both (i) comparative mechanistic information for mammalian studies as well as (ii) provide an insight into the synergistic or antagonistic effects following exposure of feral fish to complex mixtures of contaminants in the aquatic environment. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

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. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Liu IS, lohn GR, Sikora A, Lee SC, Brosnan CF (2000) Modulation of interleukin-1 beta and tumor necrosis factor alpha signaling by P2 purinergic receptors in human fetal astrocytes. 1 Neurosci 20 5292-5299... 

Pulliam L, West D, Haigwood N, Swanson RA (1993) HIV-1 envelope gpl20 alters astrocytes in human brain cultures. AIDS Res Hum Retroviruses 9 439 44 Pulliam L, Zhou M, Stubblebine M, Bitler CM (1998) Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor. J Neurosci Res 54 530-538... 

Yamashita reported anti-inflammatory effect of astaxanthin when administered with aspirin. An oral preparation has been developed by Alejung and Wadstroem for the treatment of Helicobacter infections of the mammalian gastrointestinal tract. Strong evidence suggested that astaxanthin modulated the humoral and non-humoral immune systems. It enhanced the release of interleukin-1 and tumor necrosis factor-... 

Batel R, Bihari N, Rinkevich B, Dapper J, Schaecke H, Schroeder HC, Mueller WE. 1993. Modulation of organotin-induced apoptosis by water pollutant methyl mercury in a human lymphoblastoid tumor cell hne and a marine sponge. Mar Ecol Progr Ser 93 245-251. 

Festuccia, C, V Dolo, F Guerra et al. 1998. Plasminogen activator system modulated invasive capacity and proliferation in prostatic tumor cells. Clin Exp Metastasis 16 513-528. 

Recent observations suggest that carotenoids may modulate the AP-1 activation process. It has been recently reported in mammary tumor cell lines that [3-carotene and its cleavage products were able to decrease the activation of AP-1 (Tibaduiza et al., 2002). Moreover, lycopene was also shown to downregulate AP-1 in mammary cancer cells (Karas et al., 2000). In addition, a pharmacological... 

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