Cytochrome P450-Activated Prodrugs

Montellano, Paul R. Ortiz de

doi:10.4155/fmc.12.197

Cited by 129 publications

(96 citation statements)

References 88 publications

(82 reference statements)

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“…i) The intra-CM-associated cytochrome P450 hydroxylation-activated (30,31) and intra-MM-associated cytochrome P450 hydroxylation-inactivated (31,32), sub-classified as a) The intra-CM-associated cytochrome P450 hydroxylation-activated DNA/RNA guanosine guanine alkylator procarbazine (33) (Log OWPC, -1.70; vdWD, 0.74 nm; Log OWPC-to-vdWD ratio, -2.29 nm -1 ); procarbazine hydrophilic moiety1 (Log OWPC, -0.59; vdWD, 0.51 nm; Log OWPC-to-vdWD ratio, -1.17 nm -1 ); procarbazine hydrophobic moiety1 (Log OWPC, 2.51; vdWD, 0.57 nm; Log OWPC-to-vdWD ratio, 4.43 nm -1 ); procarbazine hydrophilic moiety2 (Log OWPC, -1.11; vdWD, 0.43 nm; Log OWPC-to-vdWD ratio, -2.61 nm -1 ); procarbazine hydrophobic moiety2 (Log OWPC, 1.82; vdWD, 0.48 nm; Log OWPC-to-vdWD ratio, 3.75 nm -1 ): procarbazine alkylates DNA/RNA guanosine guanines via its CH 3 -NH 2 -NH 2 -terminal hydrophilic moiety1, but without the potential to crosslink (Table III and Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Sarin¹

2015

Molecular and Clinical Oncology

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Abstract. For proper determination of the apoptotic potential of chemoxenobiotics in synergism, it is important to understand the modes, levels and character of interactions of chemoxenobiotics with cells in the context of predicted conserved biophysical properties. Chemoxenobiotic structures are studied with respect to atom distribution over molecular space, the predicted overall octanol-to-water partition coefficient (Log OWPC; unitless) and molecular size viz a viz van der Waals diameter (vdWD). The Log OWPC-to-vdWD (nm -1 ) parameter is determined, and where applicable, hydrophilic interacting moiety/core-to-vdWD (nm -1 ) and lipophilic incorporating hydrophobic moiety/core-to-vdWD (nm -1 ) parameters of their part-structures are determined. The cellular and sub-cellular level interactions of the spectrum of xenobiotic chemotherapies have been characterized, for which a classification system has been developed based on predicted conserved biophysical properties with respect to the mode of chemotherapeutic effect. The findings of this study are applicable towards improving the effectiveness of existing combination chemotherapy regimens and the predictive accuracy of personalized cancer treatment algorithms as well as towards the selection of appropriate novel xenobiotics with the potential to be potent chemotherapeutics for dendrimer nanoparticle-based effective transvascular delivery. IntroductionSmall molecules non-endogenous to the biological system, often referred to as xenobiotics, include a diverse variety of molecules, simple organic toxicants with uncomplicated structures and natural eukaryotic antibiotics and synthetic molecules of more complicated structures and cytotoxic properties (1), the latter of which have chemotherapeutic properties. Although small molecule chemoxenobiotics, of various traditional classes, form the basis of present synergistic cancer treatment strategies, their clinical efficacy remains questionable for the treatment of solid and hematopoietic malignancies alike, upon surgical resection in the former, and during bone marrow irradiation-transplantation and after in the latter. For this reason, a better understanding of the modes and character underlying molecular cellular interactions is necessary, particularly for the purposes of improving the tumor tissue selectiveness of enhanced permeation and retention (EPR)-based chemotherapy (2), which has a prolonged blood half-life but is non-selective for solid tumor foci. Along these lines, there has been relatively recent translational advancement towards the development of optimally sized dendrimer nanoparticle-based small molecule chemotherapy at ~9 nm (H D ) (3-7), which selectively delivers small molecule chemoxenobiotics into solid malignancies at effective concentrations without systemic toxicity (4,8). As such, with optimally sized dendrimer nanoparticle-based small molecule chemotherapy, there is the potential for complete tumor regression (3,9) in lieu of the possibility for the development of drug resistance phenotypes (1...

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Section: Resultsmentioning

confidence: 99%

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Sarin¹

2015

Molecular and Clinical Oncology

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“…Presently, much of the knowledge about these enzymes is limited to their xenobiotic response, namely bioactivation of prodrugs and metabolic inactivation of drugs. Tamoxifen, cyclophosphamide, tegafur, and flutamide are some of the many anticancer agents that are administered as prodrugs [174]. Some reasons for designing chemotherapeutic agents as prodrugs include attenuating their cytotoxicity, preventing rapid degradation of their active metabolites, and achieving targeted delivery to the tumor site while sparing nontumor tissues [175,176].…”

Section: Relevance Of Cyp3a4 and Cyp3a5 To Drug Discoverymentioning

confidence: 99%

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

Lolodi

Wang

Wright

et al. 2018

CDM

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Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.

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“…It has also been shown that these enzymes play an important role as an activating factor for oxazaphosphorine agents (Ortiz de Montellano 2013). Oxazaphosphorine is a class of anticancer drugs that includes cyclophosphamide (CPA) and ifosfamide (IFA).…”

Section: Enzyme/prodrug Systemsmentioning

confidence: 99%

Enzyme/Prodrug Systems for Cancer Gene Therapy

et al. 2016

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The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings. These include slow prodrug-drug conversion rate, low transfection/transduction efficiency of the vectors and nonspecific toxicity/immunogenicity related to the delivery systems, plasmid DNA, enzymes and/or prodrugs. This mini review aims at providing an overview of the most widely used enzyme/prodrug systems with emphasis on reporting the results of the recent preclinical and clinical studies.

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Cytochrome P450-Activated Prodrugs

Cited by 129 publications

References 88 publications

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

Enzyme/Prodrug Systems for Cancer Gene Therapy

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