Tumor cell cytotoxicity

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. 

We decided to apply the elimination-based dendritic system to the synthesis of an anticancer prodrug and to evaluate it in a tumor cell cytotoxicity assay. Dendritic prodrugs 20 and 21 were synthesized with the chemotherapeutic drug melphalan as a tail unit and a trigger that is activated by PGA (Fig. 5.14). 

David, G. (2005) Covell Linking tumor cell cytotoxicity to mechanism of drug action An integrated analysis of gene expression, small-molecule screening and structural databases. Proteins Structure, Function, and Bioinformatics, 59 (3), 403-433. 

Key Words Bioinformatics chemosensitivity tumor cell cytotoxicity NC160 gene expression compoimd screen... 

Hibbs, J. B., Jr., Taintor, R. R., and Vavrin, Z. (1984). Iron depletion Possible cause of tumor cell cytotoxicity induced by activated macrophages. Biochem. Biophys. Res. Com-mun. 123, 716-723. 

Mack, M., Riethmuller, G., and Kufer, P. (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor-cell cytotoxicity. Proc. Natl Acad Sci USA 92, 7021—7025... 

Slivka, A., LoBuglio, A. F., and Weiss, S. J., A potential role for hypochlorous acid in granulocyte-mediated tumor cell cytotoxicity. Blood 55,347—350 (1980). 

Tubulin-binding agents prepared by Pinney (4) consisting of dihydronaphthalene derivatives, (IV), exhibited potent tumor cell cytotoxicity by inhibiting the polymerization of a,(3-tubulin heterodimers into the microtubule structures and were used in the treatment of proliferation diseases. 

Paclitaxel acts by enhancing microtubule assembly and stabilizing microtubules (1,2). Microtubules consist of polymers of tubulin in dynamic equilibrium with tubulin heterodimers. Their principal function is the formation of the mitotic spindle during cell division, but they are also active in many interphase functions, such as cellular motility, intracellular transport, and signal transmission. Paclitaxel inhibits the depolymerization of tubulin, and the microtubules formed in the presence of paclitaxel are extremely stable and dysfunctional. This stabilization impairs the essential assembly and disassembly required for dynamic cellular processes, and death of the cell results through disruption of the normal microtubular dynamics required for interphase processes and cell division. In tumor cells, cytotoxicity is represented by the appearance of abnormal microtubular bundles, which accumulate during G2 and mitosis, blocking the cell cycle (3). 

Henderson, W.R., Joi, E.C. and Klebanoff, S.J. (1980). Eosinophil-mediated mammalian tumor cell cytotoxicity role of the peroxidase system. J. Immunol. 124, 1949-1953. 

The anticancer effects of the stilbenoids usually involve directing cytotoxicity, inhibition of the proliferation or inducing apoptosis of the tumor cells. Cytotoxicity assay is the most commonly used preliminary anticancer protocol. 

Tumor necrosis factor-a (TNF-a) Cachectin (TNF-a) Monocytes/macs Tumor cells cytotoxicity Others similar profile of activity of IL-1 promotes antiviral state... 

Slivka A, LoBuglio AF, Weiss SJ A Potential Role for Hypochlorous Acid in Granulocyte-Mediated Tumor Cell Cytotoxicity. Blood 1980 55 347-350. 

JE Anderson, CM Goetz, JL MacLaughlin, M Suffness. A blinde comparison of simple bench-top bioassays and hnman tumor cell cytotoxicities as anti-tumor prescreenes. Phytochem Anal 2 107-111, 1991. 

Basophils are the least numerous and least well characterized of the circulating leukocytes. While they are not derived from the same progenitor cell as tissue mast cells, basophils and mast cells have several similar functions, including their participation in hypersensitivity reactions. Basophils have also been attributed roles in plasma lipolysis, parasite immunity, tumor cell cytotoxicity, and hemostasis. Increases have been associated with persistent lipemia, parasitism, allergic diseases, certain neoplastic diseases, and administration of certain drugs (e.g., heparin, penicillin). 

Anderson, J.E Goetz, C.M McLaughlin, J.L Sufness, M. A blind comparison of simple bench-top bioassays and human tumor cell cytotoxicities as anti-tumor prescreens. Phytochemical Analysis. 1991, 2, 107-111. 

Trastuzumab Binds to the HER2 protein on the surface of tumor cells. Cytotoxic for breast tumors that overexpress HER2 protein... 

Palom, Y. et al., Bioreductive metabolism of mitomycin C in EMT6 mouse mammary tumor cells cytotoxic and non-cytotoxic pathways, leading to different types of DNA adducts the effect of dicwcmol, Biochem. Pharmacol, 61,1517, 2001. 

Hurd, 1976) and has been demonstrated to mediate tumor cell cytotoxicity (Lamon et al., 1975a,b) and to bind T cells cultured in IgM-free media (Ferrarini et aL, 1976). In the latter case, binding occurred through the pentameric (Fc)5/i. 

Kim and and co-workers used ring-closing metathesis to construct the spirocyclic core of (-)-lepadiformine. (-)-Lepadiformine is a tricyclic perhydropyrrolo[2,l-y]quinolone that has recently gained attention due to its moderate in vitro tumor cell cytotoxicity and positive cardiovascular effects. Treatment of diene 183 with a catalytic amount of 4 in the presence of refluxing dichloromethane furnished the corresponding azaspiro cyclohexene 184 in near quantitative yield. 

Mouse bone marrow or peritoneal macrophages 100 pg P815 tumor cell cytotoxicity... 

A.M. Kaplan, PS. Morahan, and W. Regelson, Induction of macrophage mediated tumor cell cytotoxicity by pyran copolymer,/.Nat/. Cancer ., 52,1919-1923,1974. 

Method 2 - Solvent partitioning of crude extract. To prepare the crude cranberry extract, 100 g of frozen whole cranberries were macerated using a blender in methanol/ 2% formic acid (300 mL/100 g berries), vacuum-filtered and washed. The filtrate was lyophilized to produce a dark red semisolid crude extract. The solvent partitioning protocol of Kupchan (3) was used to separate conq)onents by polarity as follows. Crude extract (8.0 g) was first partitioned between 100 mL water and 200 mL chloroform. The water layer was further partitioned between 100 mL water and 200 mL ethyl acetate to draw some organic-soluble con onents out of aqueous solution. The chloroform extract was partitioned between 100 mL each of hexane and 90% methanol. Extracts were then dried in vacuo. Extracts were assayed for radical-scavenging activity and tumor cell cytotoxicity as described below. From 100 g berries a typical yield of 8.54 g crude extract was obtained. Partitioning of the crude extract yielded 0.201 g solids from hexane, 0.132 g from methanol, 0.631 g from ethyl acetate and 4.228 g from the aqueous layer. 

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) reduce serum cholesterol levels and cardiovascular morbidity and mortality. Statins inhibit cancer cell proliferation in in vivo tumor growth in animal models (Campbell et al. 2006 Kusama et al. 2002 Paragh et al. 2003 Sivaprasad et al. 2006). Moreover, they increased iNOS mRNA and protein expression in the human breast adenocarcinoma cell line (MCF-7). NO cytotoxicity and tumor cell cytotoxicity were inhibited by iNOS inhibitors (Kotamraju et al. 2007). Based on these data, statins which are well known as a class of hyperlipidemic blockbuster drugs and are routinely used for lowering serum cholesterol levels are potential cancer drugs for use as NO inducers. 

It is now thought that low concentrations of endogenous NO may increase tumor cell proliferation, whereas high concentrations of inducible origin NO are associated with tumor cell cytotoxicity and apoptosis (Rao 2004). The two facets of NO as an inhibitor or enhancer of tumor development have been continuously defined and reported. The principal concept required for understanding of paradoxical actions of NO in the tumor biology seems to be that of heterogeneity. As well as its concentration, chemical variability and microenvironment associated with cellular adaptation/selection to the cytotoxic actions of NO may determine the complicated cellular effect of NO. In this chapter, both cytotoxic and protective roles of NO will be discussed. 

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