Anticancer agent

An LC-MS-MS method for the simultaneous quantitative determination of actinomycin-D (Act-D) and vincristine (VCR), which are cytotoxic agents commonly used in the treatment of pediatric cancers. Following sohd-phase extraction, plasma samples are separated and analyzed using electrospray ionization (ESI). Lower limit of quantitation (LLOQ) for both Act-D and VCR 0.5 ng/ml. Analytical accuracy for detection of both Act-D and VCR 90%. Analytical precision, as estimated hy the coefficient of variation 6% for Act-D and 11% for VCR. Useful in clinical monitoring. 

LC-MS-MS was used to monitor the pharmacokinetic behavior of 5-azacitidine (5-AC), a C54idine nucleoside analog, when given with phenylhut5rate, a histone deacetylase inhibitor. Pharmacokinetic data were obtained from trials 

2 -Fluoro-5 -methyl-beta-l-arabinofuranosyl uracil triphosphate (L-FMAU-TP) 

It can be concluded that 5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors. 

An LC-MS-MS method to monitor lonafarnib (a novel anticancer drug that inhibits farnesyl transferase) in human plasma. Deuterated internal standard is used proteins are precipitated by acetonitrile. Reverse-phase chromatographic separation is performed using acetonitrile/water/formic acid (50 50 0.05, v/v/v) mobile phase. Time of analysis 8 min. A triple quadrupole tandem mass spectrometer in the positive-ion mode with multiple reaction monitoring is used for detection. The cahbration curve has been established in the 2.5-2500 ng/ml concentration range. The validated method was successfully used in phase I trials of the drug. 

CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, 

This chapter describes the clinical properties of cisplatin, and of its analogues that have undergone extensive clinical trials (particularly carboplatin), platinum chemistry relating to mechanism of action, the mechanisms of tumour resistance to cisplatin and their circumvention. 

Cisplatin was introduced into clinical practice in 1971 (only some five years after the initial discovery of its cell-killing properties), and the less toxic analogue, carboplatin, in 1981. To date, carboplatin is the only platinum analogue to have received worldwide registration. Comparative clinical properties of cisplatin and carboplatin are summarised in Table 1. 

Undoubtedly the most dramatic impact of cisplatin has been observed in men presenting with testicular cancer. Before 1975, the cure of such patients, who are predominately young adults, was rare. Following the introduction of cisplatin into a regimen also containing vinblastine and bleomycin (PVB regime), around 85% of these patients now are essentially cured of the disease. 

Initial studies at the Royal Marsden Hospital (London) by Wiltshaw and 

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Inositols, ie, hexaliydrobenzenehexols, are sugars that have received increasing study and are useful in the treatment of a wide variety of human disorders, including vascular disease, cancer, cirrhosis of the Hver, frostbite, and muscular dystrophy (269). Myoinositol esters prepared by reaction with lower fatty acid anhydrides are useful as Hver medicines and nonionic surfactants the aluminum and ammonium salts of inositol hexasulfate are useful anticancer agents (270). Tetraarjloxybenzoquinones are intermediates in the preparation of dioxazine dyes (266,271). The synthesis of hexakis(aryloxy)benzenes has also beenpubUshed (272). 

Y. Komoda and T. Kishi, in J. M. Cassady andJ. D. Douros, eds.. Anticancer Agents Based on Natural Products Models, Academic Press, New York, 1980, Chapt. 10. 

Antimetabolites. AntimetaboHtes, which represent one of the earliest groups of anticancer agents, are Hsted ia Table 1. Stmctures are showa... 

W. Wierenga "DNA-Minor Groove Binding Anticancer Agents" in Cytotoxic Mnticancer Drugs Models and Conceptsfor Drug Discovey and Development, Kluwer Academic PubHshers, Boston, Mass., 1992, p. 105. 

Pnor to 1975, discussions of fluonnatcd pharmaceuticals focused mainly on anti-mflammatory steroids, antipsychotic phenothiazines, and 5-fluorouraciI and Its derivatives as anticancer agents [/ 2] Dunng the past 25 years, and especially in the last decade, tluonnated dmgs have been marketed for the treatment of a wide variety of diseases This section will focus on those presently marketed drugs where the presence of fluonne has produced significant therapeuhc advantages... 

A notable exploitation of this reaction has been used for the preparation of potential anticancer agents. In an attempt to control the water solubility of thiophene analogs, a series of sodium salts of 2,5-dicarboethoxy-3,4-dihydroxythiophene have been produced by condensation between thiodiglycolate esters and diethyloxalate. These condensation reactions consistently proceeded in good yield. 

Several tetrahydroquinazoline analogs of folic acid were synthesized by Baker and co-workers as potential anticancer agents, and the substance (61), at 50 m/ g/ml, gave a 50% inhibition of growth of Streptococcus faecalis on a Flynn folic acid medium containing 3 m/i,g of folic acid. 

Novel bioreductive anticancer agents based on indolequinones 97F271. 

Development of anew indolocarbazole anticancer agent (NB-506) 97YGK566. 

Ng R, Better N, Green MD (2006) Anticancer agents and cardiotoxicity. Semin Oncol 33 2-14... 

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

Many anticancer agents currently in use, including chemotherapeutic drugs and radiation, are potent inducers of apoptosis and cell-cycle arrest. It is believed that induction of these molecular pathways is central to the efficacy of such agents [1]. Genetic and epigenetic alterations that contribute to tumorigenesis... 

Brown JM, Wouters BG (1999) Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59 1391-1399... 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Hsp90 is a molecular chaperon required for the refolding of proteins in cells exposed to environmental stress. It contains an ATP-binding pocket in its amino terminus. Several natural products, for example radicicol (230) (Scheme 48), bind to this pocket and inhibit its chaperon function, which is mirrored in enhanced proteosomal degradation of Hsp90 client proteins, so that compounds like 230 are of interest as novel anticancer agents. 

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