Drug Latentiation

Harper, N. J.

doi:10.1007/978-3-0348-7044-3_2

Cited by 18 publications

(21 citation statements)

References 185 publications

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“…This promiscuous reaction with DNA accounts for many of the numerous deleterious side-effects of chemotherapy and has accelerated the search for drugs that are more selective for cancer cells. Prodrugs, first introduced by Albert (Albert, 1958) and Harper (Harper, 1962), are drugs that are chemically altered to enter cells in an inert, nontoxic form and only via enzymatic interactions or through extra-cellular conditions become activated into the toxic, therapeutic form of the drug, thereby increasing the specificity for cancer cells. Cancerous cells typically have a hypoxic, reducing environment, a factor that has promoted the development of bioreductive prodrugs, specifically drugs that are reduced in a low-oxygen environment and are unreactive in healthy, well oxygenated cells (McKeown et al, 2007).…”

Section: Characterization Of Dna/drug Adducts By Tandem Mass Specmentioning

confidence: 99%

Tandem mass spectrometry for characterization of covalent adducts of DNA with anticancer therapeutics

Silvestri

Brodbelt

2012

Mass Spectrometry Reviews

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The chemotherapeutic activities of many anticancer and antibacterial drugs arise from their interactions with nucleic acid substrates. Some of these ligands interact with DNA in a way that causes conformational changes or damage to the nucleic acid targets, ultimately altering recognition by key DNA-specific enzymes, interfering with DNA transcription or prohibiting replication, and terminating cell growth and proliferation. The design and synthesis of ligands that bind to nucleic acids remains a dynamic field in medicinal chemistry and pharmaceutical research. The quest for more selective and efficacious DNA-interactive anti-cancer chemotherapeutics has likewise catalyzed the need for sensitive analytical methods that can provide structural information about the nature of the resulting DNA adducts and provide insight into the mechanistic pathways of the DNA/drug interactions and the impact on the cellular processes in biological systems. This review focuses on the array of tandem mass spectrometric strategies developed and applied for characterization of covalent adducts formed between DNA and anti-cancer ligands.

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Section: Characterization Of Dna/drug Adducts By Tandem Mass Specmentioning

confidence: 99%

Tandem mass spectrometry for characterization of covalent adducts of DNA with anticancer therapeutics

Silvestri

Brodbelt

2012

Mass Spectrometry Reviews

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“…The term latentiation was first used to describe inactive compounds that required biotransformation before they could carry out their biological function (Albert, 1958;Harper, 1959). The compounds covered by this designation, known as prodrugs, are inactive by nature, and as such are not designed to function (Stella et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

Parise-Filho

Polli

Barberato‐Filho

et al. 2010

Braz. J. Pharm. Sci.

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The aim of this paper was to emphasize the importance of prodrug design to therapy, by examining examples available on the Brazilian pharmaceutical market. The principles of prodrug design are briefly discussed herein. Examples of prodrugs from many important therapeutic classes are shown and their advantages relative to the drugs they are derived from are also discussed. Considering the importance of these therapeutic classes, from both therapy and economic standpoints, prodrug design is a very valuable aspect in the research of new drugs and for the pharmaceutical industry as a whole.Uniterms: Prodrug design. Molecular modification. Drug development.O objetivo do trabalho foi ressaltar a importância do planejamento de pró-fármacos para a terapia, por meio de exemplos disponíveis no mercado farmacêutico brasileiro. Os princípios da latenciação são sucintamente discutidos. Apresentam-se exemplos de pró-fármacos de muitas classes terapêuticas importantes e as vantagens relativas aos fármacos dos quais derivam são, também, discutidas. Considerando-se a importância dessas classes terapêuticas, tanto do aspecto terapêutico quanto do econômico, o planejamento de pró-fármacos representa aspecto de grande valor na busca de novos fármacos e na indústria farmacêutica como um todo.Uniterms: Pró-fármacos/planejamento Fármacos/latenciação. Modificação molecular. Fármacos/ desenvolvimento.

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“…ONE APPROACH TO THE problem of the lack of selectivity of cytotoxic drugs has been to attempt to synthesize agents which are activated more efficiently in tumours than in normal tissues (Harper, 1959;Ross, 1974;Workman & Double, 1978). The rational design of such latent anti-tumour agents, however, has been hindered by the lack of appropriate information on the comparative biochemistry of such vital normal tissues as marrow and intestinal mucosa (Workman & Double, 1978).…”

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confidence: 99%

Response of a high-glucuronidase human tumour xenograft to aniline mustard

Warenius¹,

Workman²,

Bleehen³

1982

Br J Cancer

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Summary.-The HT29R colonic adenocarcinoma xenograft has been shown to be rich in the enzyme p-glucuronidase. Experiments in rodent systems have demonstrated a marked anti-tumour effect of the drug aniline mustard (AM) on tumours with high levels of this enzyme (e.g. the plasmacytomas PC5 and PC6).We have found that AM is no more effective than its analogue paramethyl aniline mustard (PMAM) or other alkykating agents against the HT29R xenograft.Amongst the possible explanations for this may be: (1) The wide shoulder on the cell-survival curve shown for exposure to alkylating agents of HT29R in vivo.(2) Lack of correlation between physiological availability of P-glucuronidase and the high levels measured by the standard assay.

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Drug Latentiation

Cited by 18 publications

References 185 publications

Tandem mass spectrometry for characterization of covalent adducts of DNA with anticancer therapeutics

Tandem mass spectrometry for characterization of covalent adducts of DNA with anticancer therapeutics

Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

Response of a high-glucuronidase human tumour xenograft to aniline mustard

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