Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Musser, Steven M.; Pan, Su‐Shu; Egorin, Merrill J.; Kyle, Donald J.; Callery, Patrick S.

doi:10.1021/tx00025a016

Cited by 30 publications

(12 citation statements)

References 20 publications

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“…Other GDEPT prodrugs, such as CMDA (2chloroethyl, 2-mesyloxyethylaminobenzoyl-L-glutamic acid, activated by carboxypeptidase G2) and CB1854 (activated by P450 GDEPT may also be applicable to those established anticancer agents, which while not absolutely requiring P450 metabolism for activity, are nevertheless transformed to a more active derivative when metabolized by P450. Examples of this class of drugs include the following prodrug-P450 gene combinations: thio-TEPA, which is activated by a CYP2B-catalyzed oxidative desulfuration reaction [44], and perhaps also by metabolism leading to release of reactive aziridine moieties [45]; etoposide (VP-16), which is converted to a reactive catechol by a P450-catalyzed nitroreductase) have not been approved for human use. The ultimate clinical effectiveness of these agents in treating human cancers thus remains to be established.…”

Section: ) Compatibility With a Wide Range Of Established And Investmentioning

confidence: 99%

Cytochrome P450 Gene-directed Enzyme Prodrug Therapy (GDEPT) for Cancer

Chen¹,

Waxman²

2002

CPD

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Several commonly used cancer chemotherapeutic prodrugs, including cyclophosphamide and ifosfamide, are metabolized in the liver by a cytochrome P450 (CYP)-catalyzed prodrug activation reaction that is required for therapeutic activity. Preclinical studies have shown that the chemosensitivity of tumors to these prodrugs can be dramatically increased by P450 gene transfer, which confers the capability to activate the prodrug directly within the target tissue. This P450 gene-directed enzyme prodrug therapy (P450 GDEPT) greatly enhances the therapeutic effect of P450-activated anti-cancer prodrugs without increasing host toxicity associated with systemic distribution of active drug metabolites formed by the liver. The efficacy of P450 GDEPT can be enhanced by further increasing the partition ratio for tumor:liver prodrug activation in favor of increased intratumoral metabolism. This can be achieved by co-expression of P450 with the flavoenzyme NADPH-P450 reductase, which increases P450 metabolic activity, by localized prodrug delivery, or by the selective pharmacologic inhibition of liver prodrug activation. P450 GDEPT prodrug substrates are diverse in their structure, mechanism of action, and optimal prodrug-activating P450 gene; they include both established and investigational anticancer prodrugs, as well as bioreductive drugs that can be activated by P450/P450 reductase in a hypoxic tumor environment. Several strategies may be employed to achieve the tumor-selective gene delivery that is required for the success of P450 GDEPT; these include the use of tumor-targeted cellular vectors and tumor-selective oncolytic viruses. Overall, P450-based GDEPT presents several important, practical advantages over other GDEPT strategies that should facilitate the incorporation of P450 GDEPT into existing cancer treatment regimens. A recent report of clinical efficacy in a P450-based phase I/II gene therapy trial for pancreatic cancer patients supports this conclusion.

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Section: ) Compatibility With a Wide Range Of Established And Investmentioning

confidence: 99%

Cytochrome P450 Gene-directed Enzyme Prodrug Therapy (GDEPT) for Cancer

Chen¹,

Waxman²

2002

CPD

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“…30 A key question, which we address in this paper, is how chemotherapeutic agents with diverse molecular targets interact with the bcl-2 family-regulated survival system. Thiotepa is a classical DNA directed alkylating agent 31,32 currently used in`high dose' therapy approaches to the treatment of both hematopoietic and solid tumors. Thiotepa induces S-phase cell cycle arrest and cell death as a result of DNA cross-links or adducts formation.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels

et al. 2000

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To define the responses of apoptotic regulatory proteins to different chemotherapeutic agents, we investigated the expression of Bcl-2 family gene products, the release of cytochrome c, and the activation of pro-caspase-3 during apoptosis induced by Taxol and Thiotepa, in the MCF-7 breast carcinoma and the HL-60 leukemia cell lines. The earliest event induced by drug exposure was increase in Bad protein levels, followed by Bcl-2 down-regulation, cytochrome c release, and Bcl-x L and Bax up-regulation. Bak accumulation was a late event. Activation of pro-caspase-3 and cleavage of Bcl-2 protein occurred in the HL-60 cells only, and followed the cytochrome c release. The overall responses were qualitatively similar in both cell types, but MCF-7 cells treated with Taxol showed a significant delay in apoptosis, correlating with early up-regulation of Bcl-2 and delayed release of cytochrome c. We conclude that Bad up-regulation is an early indicator of a cellular response that will lead to cell death, but may be modulated by survival mechanisms, which cumulatively govern the ultimate susceptibility to apoptosis. Cell Death and Differentiation (2000) 7, 574 ± 586.

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“…Both thiotepa and aziridine alkylate guanine at the N 7 position (25). Another study has shown that the expression of FPG and hOGG1 protects murine fibroblasts from the lethal effect of BCNU (40).…”

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confidence: 99%

Escherichia coliFPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells

Kobune³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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To increase the resistance of lung cells to BCNU, we employed gene transfer of Escherichia coli formamidopyrimidine-DNA glycosylase (FPG) and human 8-oxoguanine-DNA glycosylase (hOGG1) to A549 cells, a lung epithelial cell line, using a bicistronic retroviral vector, pSF91-RE, that encoded both FPG/hOGG1 and an enhanced green fluorescent protein. The transduced epithelial cells were sorted by flow cytometry, and expression of FPG/hOGG1 protein was determined by the level of FPG/hOGG1 RNA and enzyme activity. The single-cell gel electrophoresis (comet assay) measured DNA damage induced by BCNU. FPG/hOGG1-expressing A549 cells incubated with 40-500 g/ml BCNU exhibited significantly less DNA damage than vector-transduced cells. In addition, FPG-and/or hOGG1-expressing cells incubated with 10-40 g/ml BCNU showed at least a 25% increase in cell survival. Gene transfer of FPG/hOGG1 reduced BCNUinduced DNA damage and cytotoxicity of cultured lung cells and may suggest a new mechanism to reduce BCNU pulmonary toxicity. deoxyribonucleic acid repair; pulmonary toxicity; N 7 -alkylated guanine; formamidopyrimidine-DNA glycosylase; human 8-oxoguanine-DNA glycosylase; 1,3-N,NЈ-bis(2-chloroethyl)-N-nitrosourea PULMONARY COMPLICATIONS of cancer chemotherapy are common (36). Although many chemotherapeutic drugs damage DNA in neoplastic cells, these drugs can also damage DNA in normal lung cells, resulting in both early-onset and delayed-onset pulmonary disorders (36). Because pulmonary toxicity remains one of the major adverse reactions limiting the use of more aggressive anticancer regimens (36), correcting or preventing the genotoxic and/or cytotoxic effects to lung cells would likely improve the therapeutic efficacy of these regimens.1,3-N,NЈ-bis(2-chloroethyl)-N-nitrosourea (BCNU) is a chemotherapeutic drug commonly used for human intracranial tumors, Hodgkin's disease, non-Hodgkin's lymphomas, melanoma, and gastrointestinal cancer (34,36). In addition to bone marrow suppression and gastrointestinal toxicity, pulmonary toxicity by BCNU is a major fatal complication and occurs in as high as 20-30% of the patients treated by BCNU (34,35). Proposed mechanisms of BCNU-induced pulmonary toxicity include DNA damage, glutathione depletion, or adverse inflammation and an immune response in the lung (6, 22). The pathological changes of BCNU-induced pulmonary toxicity include alveolar edema and protein accumulation, diffuse hyperplasia, and hypertrophy of alveolar epithelial cells, metaplasia of alveolar epithelium, fibroblastic proliferation in the alveolar septae, and alveolar septal fibrosis (23,35).As an alkylating agent, BCNU causes DNA damage by modifying bases, cross-linking, and inducing DNA strand breaks (37). BCNU alkylates DNA predominantly (Ͼ90%) at N 7 positions of guanine and to a less extent, at the O 6 position of guanine (32). O 6 adducts result in miscoding and subsequently cause interstrand cross-linking as well, so they account for both mutagenic and cytotoxic activities of BCNU (37). The O 6 guanine adducts gener...

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Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide

Cited by 30 publications

References 20 publications

Cytochrome P450 Gene-directed Enzyme Prodrug Therapy (GDEPT) for Cancer

Cytochrome P450 Gene-directed Enzyme Prodrug Therapy (GDEPT) for Cancer

Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-xL protein levels

Escherichia coliFPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells

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