Chemotherapeutic Action of a Cyclic Nitrogen Mustard Phosphamide Ester (B 518-ASTA) in Experimental Tumours of the Rat

Arnold, Herbert; Bourseaux, Friedrich; Brock, N

doi:10.1038/181931a0

Cited by 148 publications

(68 citation statements)

References 2 publications

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“…Given that CYP metabolites act as alkylating agents mainly because of cross-linking of strands of DNA, 24,25 we further investigated 4-HC-induced DNA changes. Acquired mitochondrial DNA mutations are typically mediated through reactive oxygen species, 69 which persist as long-term in vivo markers in human skin.…”

Section: -Hc Induces the Mitochondrial Common Dna Deletionmentioning

confidence: 99%

“…Given the wealth of clinical and animal data now available on CYP-induced CIA in human and mouse, 2,6,7,9 -14,17-19,23 we opted for cyclophosphamide [cis-(Ϯ-2-bis(2-chloroethyl)amino)tetrahydro-2-oxide-2H-1,3,2-oxazaphosphorine] as a reference test substance-the gold standard alkylating agent 24,25 that has long been used in clinical oncology and beyond. 2,25 In vivo, metabolism and activation of the drug occurs via the hepatic microsomal cytochrome P450 system.…”

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confidence: 99%

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Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Bodó

Tobin

Kamenisch

et al. 2007

The American Journal of Pathology

106

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Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapyinduced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF. (Am J Pathol

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Section: -Hc Induces the Mitochondrial Common Dna Deletionmentioning

confidence: 99%

mentioning

confidence: 99%

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Bodó

Tobin

Kamenisch

et al. 2007

The American Journal of Pathology

106

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“…These compounds also exhibit pesticidal activity [7]. The N-phosphorylated nitrogen mustard compounds possess anticancer activity [8][9][10][11], and substituted ureas of type RR'P(O)NHCONR"R"' exhibit pesticidal activity [12][13][14]. Belonging to this class of com-pounds, 2 -substituted 2,3 -dihydro -1H-naphtho [1,8-de]-1,2-diazaphosphorine 2-oxides and sulphides (DND) (presented in Fig.…”

Section: Introductionmentioning

confidence: 99%

QSAR studies of 2-substituted 2,3-dihydro-1h-naphtho[1,8-de]-1,3,2-diazaphosphorine 2-oxides and sulphides

et al. 2004

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A quantitative structure activity relationship (QSAR) study of 2-substituted 2,3-dihydro-1H-naphtho[1,8,de]-1,3,2-diazaphosphorine 2-oxides and sulphides (DND), examines the extent of the contribution by various physicochemical parameters with respect to their antimicrobial activity. Simple bivariant regression analysis, based on the least squares method, is applied in order to predict models. The predicted models reveal that the steric factor, MR, is the major contributor influencing antimicrobial activity. Bulky groups at the C-19 (C=O group) position positively influence the potency of the compounds.

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“…Cyclophosphamide (CPA) is a widely used antitumour drug. The compound has virtually no cytotoxic activity against mammalian cell cultures (Arnold, Bourseaux & Brock, 1958) and only the products of its oxidation at C(4) are presumed to be responsible for the activation of CPA (Hill, Laster & Struck, 1972). 4-Methylcyclophosphamide is of interest since the methyl group prevents further oxidation, so 0567-7408/81/051136-03501.00 the substitution must affect the biological activity.…”

mentioning

confidence: 99%