Doxorubicin compound

Fig. 20.10. Enhancement of doxorubicin cytotoxicity in LoVo-resistant cells by verapamil and analogues. (Adapted from Ref. [77]). The results are expressed as fold increase in cytotoxicity represented by the ratio of doxorubicin IC50 in the absence and presence of verapamil and analogues (solid bars). The verapamil concentrations used were the minimal cytotoxic concentrations (IC20)-The compounds used were verapamil (1) ...

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

The binding of substances to DNA has been used for the treatment of cancer. Such compounds might intercalate into the DNA (such as doxorubicin) or bind to the minor groove of the DNA helix (see Figure 2.2-3), thereby disturbing either duplication of DNA or transcription into mRNA. 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

Beck has contributed an incisive review of investigations from his laboratory and those of other scientists on the cellular pharmacological aspects of resistance to vinblastine and related compounds (76). Important cellular characteristics that are frequently associated with resistance to vinblastine include cross-resistance, not only to closely related compounds such as vincristine and vindesine but also to other basic naturally occurring compounds. Concomitant resistance to vinblastine and representative anthracyclines (e.g., doxorubicin) may involve reduced abilities... 

Alkylating agents are compounds capable of reacting covalently with DNA bases. If a compound of this type contains two reactive groups, intramolecular or intermolecular crosslinking of the DNA double helix and bending of the double strand occurs. Examples of this type shown here are cyclophosphamide and the inorganic complex cisplatin. Anthracyclines such as doxorubicin (adriamy-cin) insert themselves non-covalently between the bases and thus lead to local alterations in the DNA structure (see p. 254 B). 

The anthracyclines, apart from valrubicin, are administered intravenously. Doxorubicin is rapidly distributed to tissues and slowly eliminated in faeces and urine with an elimination half-life of several days. Daunorubicin undergoes extensive metabolism in the liver, among others to the active daunorubi-cinol, and is eliminated as inactive products with an elimination half-live of approximately 30 hours. Epimbicin and idambicin have similar kinetic profiles as daunombicin with respectively epirubici-nol and idarubicinol as their major metabolic products. The kinetic behavior of mitoxantrone resembles more that of doxorubicin with a very slow elimination from the body mainly as parent compound or as inactive metabolites. The anthracyclines do not cross the blood-brain barrier. 

Idarubicin (Idamycin) differs from its parent compound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mechanisms of action and resistance are similar to those of doxorubicin and daunorubicin however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabolism and biliary excretion. Adverse reactions of idarubicin are similar to those of its congeners. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Reconstitution of full-length BRCAl into mouse embryonic fibroblast cells with a disrupted BRCAl led to an increase in resistance to several DNA damaging agents, including the platinum compounds carboplatin and oxaliplatin, the topoisomerase 1 drugs irinotecan and topotecan, and the topoisomerase 11 drugs doxorubicin and etoposide (61). 

The dimers were studied more closely in HL-60 leukaemia and Jurkat cell lines, and it was found that they have activities comparable to the clinically used anticancer chug doxorubicin. In terms of general toxicity to normal cells, it was observed that dimers 115 and 116 were not toxic to lymphocytes at doses approaching 100 p,M. In preliminary studies, apoptotic cell death was observed on exposure to these compounds and further studies are ongoing to elucidate the underlying mechanism of apoptosis. For purposes of comparison, the corresponding phosphate ester monomers 117 and 118 were prepared and proved to have no antitumour activity in the cell lines examined. This result is important, because it rules out any role of the phosphate ester functionality in mediating the observed cytotoxic effects and emphasizes the necessity for a bivalent unit. 

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