Resistance, cancer

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

Tumor cells may become resistant when genetic changes occur during cell proliferation. Resistant cancer cells with the mdr-1 gene may possess a membrane-associated protein, p-glycoprotein, that facilitates efflux of chemotherapy agents out of the cells. Numerous attempts at blocking this efflux pump have been unsuccessful. 

An other example of Salvia quinone is salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, which is cytotoxic against multidrug-resistant cancer cell lines of topoisomerase II inhibition by trapping the DNA-topoisomerase II complex (49). 

Kudoh K et al. Monitoring the expression profiles of doxorubicin-induced and doxombicin-resistant cancer cells by cDNA microarray. Cancer Res 2000 60 4161-4166. 

Allen JD, Brinkhuis RF, van Deemter L, Wijnholds J, Schinkel AH. Extensive contribution of the multidmg transporters P-glycoprotein and Mrpl to basal drug resistance. Cancer Res 2000 60(20) 5761-5766. 

Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998 252(1)703-110. 

Numerous and disparate copper criteria are proposed for protecting the health of agricultural crops, aquatic life, terrestrial invertebrates, poultry, laboratory white rats, and humans (Table 3.8) however, no copper criteria are now available for protection of avian and mammalian wildlife, and this needs to be rectified. Several of the proposed criteria do not adequately protect sensitive species of plants and animals and need to be reexamined. Other research areas that merit additional effort include biomarkers of early copper stress copper interactions with interrelated trace elements in cases of deficiency and excess copper status effects on disease resistance, cancer, mutagenicity, and birth defects mechanisms of copper tolerance or acclimatization and chemical speciation of copper, including measurement of flux rates of ionic copper from metallic copper. 

Lucci A, Giuliano AE, Han TY, Dinur T, Liu YY, Senchenkov A, Cabot MC (1999) Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells. Int J Oncol 15(3) 535-540... 

Y. Lavie, G. Fiucci, and M. Liscovitch. Up-regulation of caveolae and caveloar constituents in multidrug-resistant cancer cells. J. Biol. Chem. 213. 32380-32383 (1998). 

Y. Lavie and M. Liscovitch. Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences. Glycoconj. J. 17 253-259 (2000). 

Cabot, M. C., Giulano, A. E., Han, T-Y., and Liu, Y-Y., 1999, SDZ PSC 833, the cyclosporin A analog and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drag-resistant cancer cells. Cancer Res. 59 880-885. 

Lucci, A., Han, T. Y., Liu, Y. Y., Giuliano, A. R, and Cabot, M. C., 1999b, Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 86 299-310. 

Cyclopamine also interferes with cholesterol metabolism that results in decreased cholesterol synthesis and the accumulation of late biosynthetic intermediates. Cyclopamine was evaluated as an inhibitor of multi-drug resistance in tumor cells. Intrinsic or acquired resistance of tumor cells to cytotoxic drugs is a major cause of failure of chemotherapy. Both cyclopamine and the spirosolane alkaloid tomatidine from tomatoes act as potent and elfective chemosensitizers in multidrug-resistant cells (Lavie et ah, 2001). Therefore, plant steroidal alkaloids, such as cyclopamine and tomatidine, or their analogs, may serve as chemosensitizers in combination with chemotherapy and conventional cytotoxic drugs for treating multidrug-resistant cancers. 

Allen, J. D., Jackson, S. C., and Schinkel, A. H. (2002) A mutation hot spot in the BCRPl (ABCG2) multidrug transporter in mouse cell fines selected for doxorubicin resistance. Cancer Res. 62, 2294-2299. 

Nakamura, Y., Oka, M., Soda, H., et al. (2005) Gefitinib ( Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ ABCG2-mediated drug resistance. Cancer Res. 65, 1541-1546. 

Herzog, C. E. and Bates, S. E. (1994) Molecular diagnosis of multidrug resistance. Cancer Treat Res. 73,129-147. 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Dwivedi RS, Wang LJ, Mirkin BL (1999) S-adenosylmethionine synthetase is overexpressed in murine neuroblastoma cells resistant to nudeoside analogue inhibitors of S-adenosylhomocysteine hydrolase a novel mechanism of drug resistance. Cancer Res 56 1852-1856... 

Hu YP, Robert J (1997) Inhibition of protein kinase C in multidrug-resistant cells by modulators of multidrug resistance.) Cancer Res Clin Oncol 123 201-210... 

Sampson E, Wolff CL, Abraham I (1993) Staurosporine reduces P-glycoprotein expression and modulates multidrug resistance. Cancer Lett 68 7-14... 

Tew KD (1994) Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 54 4313-4320... 

G Lehne. P-glycoprotein as a drug target in the treatment of multidrug resistant cancer. Curr Drug Targets 1 85—99, 2000. 

Andrews PA, Howell SB. Cellular pharmacology of cisplatin perspective on mechanisms of acquired resistance. Cancer Cells 1990 2 35 43. 

PanvichianR, OrthK, Day ML, Day KC, PilatMJ, PientaKJ. Paclitaxel-associatedmultimininucleation is permitted by the inhibition of caspase activation a potential early step in drug resistance. Cancer Res 1998 58(20) 4667 1672. 

Seth P, Katayose D, Li Z, et al. A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells a gene therapy approach for drug-resistant cancers. Cancer Gene Ther 1997 4 383-390. 

Kitazaki T, Oka M, Nakamura Y et al. Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. Lung Cancer 2005 49 337-343. 

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