Elliptinium Acetate in Metastatic Breast Cancer – a Phase II Study

Buzdar, Aman U.; Hortobágyi, Gabriel N.; Esparza, Laura; Holmes, Frankie A.; Ro, Jung Sil; Fraschini, Giuseppe; Lichtiger, Benjamin

doi:10.1159/000226797

Cited by 16 publications

(8 citation statements)

References 2 publications

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“…Ellipticine derivatives, 2-methyl-9-hydroxyellipticinium and retelliptine dihydrochloride, were tested in Phase I clinical trials (Gouyette et al, 1982;Kattan et al, 1994). Elliptinium acetate was tested in Phase II clinical trials and showed moderate antitumor activity in patients with metastatic breast cancer (Buzdar et al, 1990;Rouesse et al, 1993). The utility of these drugs was limited by toxicities such as nausea, hypertension, muscular cramp, EKG anomalies, xerostomia, and hemolytic reactions.…”

Section: Discussionmentioning

confidence: 99%

Rescue of mutant p53 transcription function by ellipticine

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Rescue of mutant p53 transcription function by ellipticine

et al. 2003

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“…As a Topoisomerase 2 inhibitor and intercalating agent, elliptinium stabilizes the cleavable complex of Topoisomerase 2 and induces DNA breakages, thereby inhibiting DNA reduplication and RNA synthesis. The agent has anti-tumor activity against breast, kidney, and other cancers (Buzdar et al 1990). …”

Section: Topoisomerase 2 Inhibitorsmentioning

confidence: 99%

DNA Damaging Drugs

Weber

2015

Molecular Therapies of Cancer

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The classical anti-cancer agents comprise cytotoxic compounds. Mostly, these drugs act by exerting DNA damage. In essence, there are two major response phenotypes available to a cell upon DNA damage, such as a chemotherapeutic drug action, -to arrest the cell cycle and repair the damage, -to initiate a pathway to apoptosis (programmed cell death).In either scenario, the uncontrolled growth of the tumor cells is curtailed. The major limitation of the cytotoxic anti-cancer drugs is the tumor non-specific action, and the suppression of all rapidly dividing cells 1 . Alkylating AgentsAlkylating agents 2 are electrophilic and bind covalently to electron-rich functional groups of various target molecules via first-order or second-order nucleophilic substitutions (nucleophiles are electron-rich molecules or ions, such as OH − , H 2 O, halogenides, alcohols, thiols and amines). The first order reactants include aromatic and aliphatic nitrogen and sulfur mustards. Second order reactants include ethylene 1 Because the desired drug actions (damage to rapidly proliferating cancer cells) and the adverse effects (damage to rapidly proliferating healthy cells) are identical in targets and mechanisms, they are not separable. 2 Alkyl designates a functional group (a "side chain") that consists solely of single-bonded carbon and hydrogen atoms. Alkylating anticancer agents attach alkyl groups to biomolecules. imines and epoxides, alkylmethane sulfonates of the busulfan (Myleran) type, and α-halogenated acids, ketones, and their derivatives.-For first-order reactions, the rate limiting step is the ionization of the alkylating agent to form a positively charged carbonium ion, which then rapidly reacts with water, or a negative center, or a nucleophilic center. Within DNA and RNA, the most reactive site is the N 7 position of guanine ( Fig. 2.1). In DNA, this is followed by N 3 of adenine, N 1 of adenine, N 1 of cytosine, and N 7 of adenine (Table 2.1). The rate limiting step of the reaction is the formation of positively charged cyclic immonium ions, whereas the rate of the reaction is essentially independent of the nature and concentration of the nucleophilic target being attacked. -For second order nucleophilic substitutions, both reactants interact to form a transition complex. No carbonium ion is formed. The rate of the reaction depends on both concentrations, with bond strengths, electron affinity, and accessibility of both reagents being important (Knock 1967).Alkylating agents exert cytotoxic effects by transferring alkyl groups to DNA, thereby damaging the DNA and interfering with DNA transcription and cell division. This class of drugs mainly works by three distinct mechanisms:-The attachment of alkyl groups to DNA bases prevents DNA synthesis and RNA transcription, and it results in the DNA being fragmented by repair enzymes in a process to replace the altered bases. -The two arms of mustard drugs can cross-link DNA strands. In this process, two bases are linked together. Bridges can be formed within a single molecule of...

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“…Taxol is an important cancer chemotherapeutic agent for treatment of advanced ovarian and breast carcinoma, and it shows promising activity against several other carcinomas (Arbuck et al, 1994;Gelmon, 1994;Buzdar et al, 1995;Chang & Garrow, 1995;McGuire et al, 1996). It is a potent inhibitor of eukaryotic cell proliferation, blocking cell cycle progression at mitosis through its stabilizing actions on microtubules (Fuchs & Johnson, 1978;Schiff & Horwitz, 1980;Jordan et al, 1993).…”

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confidence: 99%

Taxol Differentially Modulates the Dynamics of Microtubules Assembled from Unfractionated and Purified β-Tubulin Isotypes

et al. 1997

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Substoichiometric binding of taxol to tubulin in microtubules potently suppresses microtubule dynamics, which appears to be the most sensitive antiproliferative mechanism of taxol. To determine whether the beta-tubulin isotype composition of a microtubule can modulate sensitivity to taxol, we measured the effects of substoichiometric ratios of taxol bound to tubulin in microtubules on the dynamics of microtubules composed of purified alphabeta(II)-, alphabeta(III)-, or alphabeta(IV)-tubulin isotypes and compared the results with the effects of taxol on microtubules assembled from unfractionated tubulin. Substoichiometric ratios of bound taxol in microtubules assembled from purified beta-tubulin isotypes or unfractionated tubulin potently suppressed the shortening rates and the lengths shortened per shortening event. Correlation of the suppression of the shortening rate with the stoichiometry of bound taxol revealed that microtubules composed of purified alphabeta(II)-, alphabeta(III)-, and alphabeta(IV)-tubulin were, respectively, 1.6-, 7.4-, and 7.2-fold less sensitive to the effects of bound taxol than microtubules assembled from unfractionated tubulin. These results indicate that taxol differentially modulates microtubule dynamics depending upon the beta-tubulin isotype composition. The results are consistent with recent studies correlating taxol resistance in tumor cells with increased levels of beta(III0- and beta(IV)-tubulin expression and suggest that altered cellular expression of beta-tubulin isotypes can be an important mechanism by which tumor cells develop resistance to taxol.

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Elliptinium Acetate in Metastatic Breast Cancer – a Phase II Study

Cited by 16 publications

References 2 publications

Rescue of mutant p53 transcription function by ellipticine

Rescue of mutant p53 transcription function by ellipticine

DNA Damaging Drugs

Taxol Differentially Modulates the Dynamics of Microtubules Assembled from Unfractionated and Purified β-Tubulin Isotypes

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