Anticancer drugs cytotoxic

Tab. 5.11 Potentiation by reserpine and verapamil of anticancer drug cytotoxicity in parental AA8 cells and their MDR T19 subline as determined by the clonogenic assay. (Reprinted from Tab. 1 of ref. 109 with permission from Blackwell Science)... 

Mitoxantrone] (anthraquinone) Synthetic Dansyl-CaM-FC (4) [anticancer drug, cytotoxic, immunomodulator]... 

Drori S, Eytan GD, Assaraf YG. Potentiation of anticancer-drug cytotoxicity by multidrug-resistance chemosensitizers involves alterations in membrane fluidity leading to increased membrane permeability. Eur J Biochem 1995 228 1020-1029. 

The unusual tolyporphin was isolated from the Pacific cyanophyte Tolypothrix nodosa and it has been shown that tolyporphin eliminates the multidrug resistance (MDR) in certain carcinoma sublines thus potentiating the cytotoxicity of anticancer drugs in these cell lines.2... 

Anticancer diugs Cytostatic drugs Cytotoxic drags Antitumor drags... 

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

Mata, J. F., et al. Role of the human concentrative nucleoside transporter (hCNTl) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol. Pharmacol. 2001, 59, 1542— 1548. 

This work provides important evidence for elucidating the cytotoxic effect of the ruthenium-arene complexes and the influence of the arene thereon, for instance with respect to excision repair of DNA lesions and DNA destabilization. It also established two different classes of Ru(II) arene anticancer drugs, i.e. those bearing an arene that has the possibility to intercalate and those that do not. This distinction is important as we will see further differences in DNA binding interactions for these two classes (vide infra). 

A major point that needs to be addressed in future work is the targeted delivery of organometallic anticancer drugs to cancer cells only. Also, additional features that generate cytotoxic activity other than disruption of DNA replication, such as the inclusion of molecular fragments that can interfere in cancer cell-specific cellular pathways, could be explored (11,103). 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

P-gp is expressed in tumor tissue and serves as a barrier to increased accumulation of cytotoxic anticancer drugs within the cancer cell by actively pumping the drug out of the cell. It is a multidrug resistance element by virtue of the fact that it is promiscuous in terms of substrate selectivity. It, like the cytochromes P450, will accept a wide diversity of structural types. For example, a small sampling of drugs that are substrates for P-gp... 

G. M. Dubowchik, M. A. Walker, Receptor-Mediated and Enzyme-Dependent Targeting of Cytotoxic Anticancer Drugs , Pharmacol. Ther. 1999, 83, 67- 123. 

Skehan, P. et al., New colorimetric cytotoxicity assay for anticancer-drug screening, /. Natl. Cancer Inst., 82, 1107-1112, 1990. 

Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21) 7291—7300 Komberg RD and Lorch Y (1999) Twenty-Five years of die nucleosome, fundamental particle of die eukaryote chromosome. Cell 98(3) 285—294... 

In view of the substantial current interest in drug actions at the cell membrane and the relationships between such effects and anticancer drug action, it is interesting to note that both vincristine and vinblastine produce crenellation (wrinkling) of cell membranes as a characteristic morphological effect (12). That cytotoxicity produced by treatment with vinblastine may be linked to perturbations of membrane function, suscep-... 

Of the non-antibody, non-liposome based drug targeting strategies, most of the (limited) clinical experience has been obtained with polymer-based conjugates of anticancer drugs. The most widely employed drugs for this application are cytotoxic agents such as doxorubicin and... 

---