Bioreductive therapies: an overview of drugs and their mechanisms of action

Rauth, Andrew M.; Melo, Tricia; Misra, V

doi:10.1016/s0360-3016(98)00302-2

Cited by 103 publications

(67 citation statements)

References 48 publications

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“…Entre estes, os 5-nitroimidazóis e os 2-nitroimidazóis podem ser utilizados como radiossensibilizantes, 65,68 uma vez que o grupo nitro atua como aceptor de elétrons dos radicais formados pela radiação ionizante junto ao DNA, formando radicais que ocasionam dano e quebra da dupla hélice. 5,14,69 Neste mecanismo, o evento químico que determina o efeito da radiossensibilização é o potencial de redução do grupo nitro. Outro fator importante a ser observado é a afinidade eletrônica do grupo nitro, que quanto maior for maior será a sua capacidade radiossensibilizante.…”

Section: Atividade Antineoplásicaunclassified

“…Adicionalmente, a ausência de compostos eficazes frente a doenças órfãs, como algumas doenças infecto-contagiosas e alguns tipos de câncer evidenciam as deficiências da terapêutica atual. [1][2][3][4][5] Estes fatos demonstram a necessidade premente de desenvolvimento de novos agentes bioativos, com eficácia comprovada, para o tratamento dessas enfermidades e que possuam toxicidade e efeitos colaterais compatíveis com a condição de fármaco. Neste sentido, alguns nitrocompostos, candidatos potenciais a agentes terapêuticos, destacam-se como antibacterianos, antiparasitários e até como antineoplásicos, o que ressalta a importância desta classe de compostos.…”

Section: Introductionunclassified

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Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

Paulai¹,

Serrano²,

Tavares³

2009

Quím. Nova

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Section: Atividade Antineoplásicaunclassified

Section: Introductionunclassified

Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

Paulai¹,

Serrano²,

Tavares³

2009

Quím. Nova

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“…NQO1 is a major activating enzyme for MMC and other bioreductive agents including, RH1 and MeDZQ (Workman and Stratford, 1993;Riley and Workman, 1992;Beall et al, 1995;Winski et al, 1998). Thus, selectively increasing the level of NQO1 in tumour cells by gene transfer (Rauth et al, 1998) or by selective induction of NQO1 in tumours may be useful for enhancing the efficacy of bioreductive agents. We showed previously that we could selectively increase NQO1 activity in tumour cells compared with normal cells and that this enhanced MMC antitumour activity in vitro (Doherty et al, 1998;Wang et al, 1999).…”

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confidence: 99%

Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo

et al. 2004

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The bioreductive antitumour agent, mitomycin C (MMC), requires activation by reductive enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1). We used a novel approach to increase MMC efficacy by selectively inducing NQO1 in tumour cells in vivo. CD-1 nude mice were implanted with HCT116 cells, and fed control diet or diet containing 0.3% of the NQO1 inducer, dimethyl fumarate (DMF). The mice were then treated with saline, 2.0, 3.5 or 2.0 mg kg À1 MMC and dicoumarol, an NQO1 inhibitor. The DMF diet increased NQO1 activity by 2.5-fold in the tumours, but had no effect in marrow cells. Mice given control diet/ 2.0 mg kg À1 MMC had tumours with the same volume as control mice; however, mice given DMF diet/2.0 mg kg À1 MMC had significantly smaller tumours. Tumour volumes in mice given DMF/2.0 mg kg À1 MMC were similar to those in mice given control diet/ 3.5 mg kg À1 MMC. Tumour inhibition was partially reversed in mice given DMF/2.0 mg kg À1 MMC and dicoumarol. DMF diet/ 2.0 mg kg À1 MMC treatment did not increase myelosuppression and did not produce any organ toxicity. These results provide strong evidence that dietary inducers of NQO1 can increase the antitumour activity of bioreductive agents like MMC without increasing toxicity.

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“…7 For example, bioreduction of the prodrug CB1954 by an E. coli nitroreductase to form an alkylating agent has recently given promising results in experimental tumor models. 8 In the present study, we examined whether the widely studied and clinically used drug mitomycin C (MMC ) can be used as a prodrug 9 in conjunction with human DTdiaphorase ( DTD ), which has the ability to activate MMC in cell -free systems but whose role in cells as a key activating enzyme is still controversial. 10 DTD [NAD(P )H:quinone oxidoreductase (NQO1); Enzyme Commission no.…”

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Expression of the prodrug-activating enzyme DT-diaphorase via Ad5 delivery to human colon carcinoma cells in vitro

2002

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Intratumoral injection of recombinant adenoviral type 5 ( Ad5 ) vectors that carry prodrug -activating enzymes like DT -diaphorase ( DTD ) could be used to selectively target tumor cells for chemotherapy. To demonstrate the feasibility of this approach, Ad5 vectors were constructed, which express human DTD minigenes for both wild -type and mutant ( C -to -T change in nucleotide 609 in DTD cDNA ) DTD under the control of the cytomegalovirus ( CMV ) promoter. HT29 human colon carcinoma cells express wild -type DTD, whereas BE human colon carcinoma cells express mutant DTD, have low to undetectable DTD activity, and are 4 -to 6 -fold more resistant to mitomycin C ( MMC ) than HT29 cells. A test of the ability of Ad5 to infect these cells ( using a -galactosidase CMVdriven minigene ) indicated that 90 -100% of BE cells were infected at a multiplicity of infection ( MOI ) of 100, whereas only 15 -40% of HT29 cells were infected at this MOI. Infection of BE cells in vitro with recombinant Ad5 carrying a minigene for wild -type DTD at MOIs of 3 -100 resulted in a progressive increase in DTD activity and a maximal 8 -fold increase in sensitivity to MMC as measured by a colony -forming assay. HT29 cells were sensitized 2 -to 3 -fold following treatment with Ad5.DTD at an MOI of 100. These results indicate that adenovirus -mediated gene transfer and expression of wild -type DTD can sensitize resistant tumor cells to MMC and that this therapeutic strategy may exert a significant bystander effect.

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Bioreductive therapies: an overview of drugs and their mechanisms of action

Cited by 103 publications

References 48 publications

Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

Aspectos mecanísticos da bioatividade e toxicidade de nitrocompostos

Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo

Expression of the prodrug-activating enzyme DT-diaphorase via Ad5 delivery to human colon carcinoma cells in vitro

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