Disease relevance of Phosphamide mustard

• BG also enhances the toxicity of 4-HC and PM by a mechanism that may not involve the AGT repair protein [1].
• We examined 4-hydroperoxycyclophosphamide (4HC) and phosphorodiamidic mustard (PM)-mediated cytotoxicity and DNA interstrand cross-link (ISC) induction in a 4HC-resistant subline, B5-180(3), that was derived from the subcloned human myeloid leukemia cell line KBM-7/B5 [2].
• These results extend our previous studies demonstrating the antitumor activity of nitrogen and phosphoramide mustard-based bifunctional alkylating agents in the treatment of human medulloblastoma continuous cell lines and transplantable xenografts, and support the continued use of these agents in clinical trials [3].
• Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT [4].
• Murine tumor testing of the phosphoramide mustard derivatives and two intermediates indicated that two compounds possessed marginal activity against mammary carcinoma and lymphocytic leukemia [5].

High impact information on Phosphamide mustard

• Nevertheless, both control and CY-treated AML cells demonstrated similar dose-dependent sensitivity to 100 to 500 mumol/L phosphoramide mustard (PhM), the active alkylating end-product of CY activation in vivo [6].
• BG had no effect on 4hydroperoxydidechlorocyclophosphamide (which generates acrolein and a nonalkylating form of PM) in CHO cells and CHOMIK cells, but enhancement of toxicity was observed with PM in both these cell lines [1].
• CHO cells transduced with wild-type human AGT (CHO(AGT)) and pcDNA3 (CHOpcDNA3) were treated with activated cyclophosphamide derivatives, 4-hydroperoxycyclophosphamide (4-HC), 4-hydroperoxydidechlorocyclophosphamide (4-HDC), a progenitor of acrolein, and phosphoramide mustard (PM) [7].
• The present study demonstrates that AGT plays an important role in protecting against the toxic and mutagenic effect of cyclophosphamide and suggests that acrolein, not PM, is responsible for generating the toxic and mutagenic lesion(s) protected by the AGT protein [7].
• Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values [8].

Chemical compound and disease context of Phosphamide mustard

• Although phosphoramide mustard (PM) is generally recognized as being the most genotoxic metabolite of cyclophosphamide (CP), the contribution of acrolein to the cytogenetic toxicity of CP is unclear [9].
• The toxicities of 4-hydroperoxycyclophosphamide (4-OOH CY), phosphoramide mustard (PM), melphalan (MEL) and busulphan (BU) have been compared in Chinese hamster cells, V-79-753B [10].
• 4-OH-CP toxicity results (a) from oxazaphosphorine-specific toxicity due to reactivity of the hemiaminal group with thiol groups of membrane proteins and (b) from PAM release catalysed by ubiquitous phosphodiesterases present in blood and tissues [11].

Biological context of Phosphamide mustard

• 4. The products formed on alkylation of ethanethiol by these metabolites have been identified, confirming that phosphoramide mustard undergoes alkylation reactions as an intact molecule [12].
• Effect of acrolein on phosphoramide mustard-induced sister chromatid exchanges in cultured human lymphocytes [9].
• The interpatient variability of the AUC of cyclophosphamide/phosphoramide mustard that was demonstrated was most likely a result of each individual's metabolic capacity [13].
• Thus increased levels of GST A1-1 in tumor cells can contribute to an enhanced detoxification of phosphoramide mustard and hence to the development of drug resistance [14].
• The DNA cross-linking cytotoxic metabolite phosphoramide mustard was elevated more than 2-fold in the LC (76.5 +/- 13.9%) compared with the HC (33.0 +/- 12.2%) phenotype [15].

Anatomical context of Phosphamide mustard

• The inhibitors did not potentiate the cytotoxic action of the nonoxazaphosphorines, phosphoramide mustard and acrolein, against these cell lines [16].
• Two reactive metabolites of CY which may inhibit suppressor T-cell generation are phosphoramide mustard and acrolein, compounds known to primarily bind to DNA and sulfhydryl groups, respectively [17].
• Exposure to phosphoramide mustard did not produce single strand breaks, but exposure of K562 cells to acrolein resulted in substantial levels of single strand breaks [18].
• We have studied the disposition of cyclophosphamide, its major cytotoxic metabolite phosphoramide mustard, and the synthetic glucocorticoid dexamethasone in nine patients receiving high-dose cyclophosphamide daily for 2 days before bone marrow transplantation [19].
• The present study was designed to investigate the genotoxicity of 4-hydroxycyclophosphamide (4-OHCP) and phosphoramide mustard (PAM), both reactive metabolites of cyclophosphamide (CP), for possible differences in SCE-inducing activity in mouse T- and B-lymphocytes [20].

Associations of Phosphamide mustard with other chemical compounds

• Conversion of 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein mediated by bifunctional catalysis [21].
• Our data also indicate that the induction of abnormal morphogenesis by 4-hydroperoxycyclophosphamide and phosphoramide mustard is correlated with drug-induced DNA cross-linking [22].
• The relative alkylating activities of two of the cytotoxic metabolites of cyclophosphamide, phosphoramide mustard and nornitrogen mustard, have been studied at pH 4.6 and 7 [12].
• Reaction of 2'-deoxyguanosine 3'-monophosphate and phosphoramide mustard resulted in the formation of several adducts that could be detected by high performance liquid chromatography (HPLC) [23].
• These studies establish that ifosphamide is less potent than cyclophosphamide in modulating the pattern of cytochrome P450 and steroid 5 alpha-reductase expression and that phosphoramide mustard is responsible for the modulation of liver enzyme expression by cyclophosphamide, with acrolein potentiating the modulating activity of the mustard [24].

Gene context of Phosphamide mustard

• Furthermore, two interspecific hybrids derived from UV41, both of which retained the region of human chromosome 16 that harbors the ERCC4 gene, displayed essentially wild-type resistance to 4HC and PM, confirming the importance of ERCC4 for the repair of 4HC-induced DNA damage [25].
• To confirm the importance of the ERCC1 gene for cellular resistance to 4HC and PM, UV20 cells were transfected with the human ERCC1 gene and subsequently exposed to 4HC and PM [25].
• RESULTS: The rank ordering of sensitivity to both 4HC and PM, based on the combined survival data, was UV41/UV4/UV20 > > UV61/UV24/UV135/EM9 > or = UV5 approximately AA8 [25].
• Similarly, the inhibition of proliferation was probably not related to endogenous IL-2 levels: addition of exogenous IL-2 to PM-containing cultures did not result in any restoration of proliferation [26].
• Thus, concanavalin A-stimulated lymphocytes still acquired IL-2 receptors (Tac antigen) normally in the presence of PM (10(-6) to 10(-9) M) [26].

Analytical, diagnostic and therapeutic context of Phosphamide mustard

• NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 degrees C and pH 7 [27].
• Between pH 1 and 11, both the 31P and 15N resonances for phosphoramide mustard displayed a single monobasic titration curve with a pKa of 4 [28].
• Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection [29].
• Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro [30].
• Paradoxically, however, the generation of cytotoxic lymphocytes in mixed lymphocyte reactions (MLRs) and mixed lymphocyte tumor cell cultures (MLTCs) was very resistant to PM [26].

References