Studies on the toxicity and antitumour activity of prednimustine, a prednisolone ester of chlorambucil

Harrap, K. R.; Riches, Pamela G.; Gilby, Edward D.; Sellwood, Susan M.; Wilkinson, Ray; Könyves, I.

doi:10.1016/0014-2964(77)90143-8

Cited by 45 publications

(8 citation statements)

References 12 publications

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“…Prednimustine (Leo-1031) is a steroidal alkylating agent, in which a corticosteroid (pregnadiene-dione-triol) is linked to chlorambucil. The drug has both alkylating and corticosteroid effects (Harrap et al 1977). It exerts effects in chronic lymphoid leukemia, lymphosarcoma, acute myeloid leukemia, mammary carcinoma, and melanoma.…”

Section: Steroid-coupled Nitrogen Mustardsmentioning

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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Section: Steroid-coupled Nitrogen Mustardsmentioning

confidence: 99%

DNA Damaging Drugs

Weber

2015

Molecular Therapies of Cancer

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“…Synergism would occur in protocol 2 if the presence of steroid could potentiate minor damage caused by Ara-C to a degree which results in cell death. Such a mechanism would be similar to the synergism between glucocorticoids and various alkylating agents which has been observed in cells which are not lysed by glu,cocorticoids (Harrap et al, 1977; Shepherd & Harrap, 1982;Tew et al, 1982). Since both Ara-C and the alkylating agents are known to damage DNA, it is possible that glucocorticoids interfere with DNA repair mechanisms and so diminish the ability of cells to recover from exposure to these drugs.…”

Section: Discussionmentioning

confidence: 90%

Synergistic killing of human leukaemic lymphoblasts by glucocorticoids and cytosine arabinoside

Gledhill¹,

Edwards²,

Norman³

1983

Br J Cancer

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Summary Previous work has shown that the lethal effects of glucocorticoids on the human lymphoblastoid cell line, CEM-C7, are antagonized by the simultaneous presence of 1-,B-D-arabinofuranosylcytosine (Ara-C). A possible cell cycle mechanism prompted further studies using flow microfluorimetry. We now report that (1) Ara-C (10-100nM) blocks cells in S-phase and (2) the block is reversible after the drug is removed. A second treatment protocol, in which glucocorticoid is added to cells recovering from the effects of 24h exposure to Ara-C, results in a clear synergism between the 2 drugs. This synergism is observed over a range of concentrations (5-100nM), but is most significant at low doses, where inhibition of cell growth by Ara-C occurs but cell killing is minimal. Prior treatment with Ara-C increases the number of cells killed in the presence of steroid during the period 12-24h after removal of the S-phase block. Combinations of Ara-C and steroid can thus be either synergistic or antagonistic, depending on the drug scheduling.

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“…Конъюгат преднизолона и хлорамбуцила -преднимустин 8 -оказался намного эффективнее, чем хлорамбуцил против саркомы Иошида, но на саркому Эрлиха, устойчивую к хлорамбуцилу, преднимустин не действовал [41][42][43][44][45]. Бестрабуцил 9 накапливался в опухоли в 5-10 раз активнее, чем в неповрежденной ткани [46]. Конъюгаты гомо-А-азастероидов 10 и 11 были активны против карциномы Эрлиха, нескольких линий аденокарциномы толстой кишки и легких; оба конъюгата подавляли рост лимфолейкоза Р338, но только конъюгат 10 латестоксат был активен против лимфолейкоза L1210 [47][48][49].…”

Section: конъюгаты стероидов с лекарственными препаратамиunclassified

Steroid Conjugates as Potential Anti-Cancer Agents

Zolottsev

Latysheva

Покровский

et al. 2020

Rossijskij bioterapevtičeskij žurnal

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The review is dedicated to results of investigations of steroid conjugates published predominantly over the past decade. It consists of three parts in which the data concerning biological activity of steroid conjugates with known drugs, steroid dimers, and steroid conjugates with some natural compounds, their fragments and related derivatives and analogs, are discussed. The structures of 231 steroid conjugates and their anti-cancer properties are presented.

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Studies on the toxicity and antitumour activity of prednimustine, a prednisolone ester of chlorambucil

Cited by 45 publications

References 12 publications

DNA Damaging Drugs

DNA Damaging Drugs

Synergistic killing of human leukaemic lymphoblasts by glucocorticoids and cytosine arabinoside

Steroid Conjugates as Potential Anti-Cancer Agents

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