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Results for “NITROGEN MUSTARDS”

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PubMed1995

DNA repair enzyme expression in chronic lymphocytic leukemia vis-à-vis nitrogen mustard drug resistance.

Nitrogen mustard resistance in B-cell chronic lymphocytic leukemia (B-CLL) has been associated with enhanced DNA repair and increased expression of DNA repair enzymes. Lymphocytes from patients with nitrogen mustard resistant B-CLL displayed a fivefold increase in resistance to melphalan in vitro as compared to those from untreated patients concordant with our definition of clinical resistance. We have performed Northern analysis using a cohort consisting of 11 untreated and 12 treated-resistant patients. Increased expression of ERCC-1 was not found to be associated with nitrogen mustard resistance, nor did we find altered expression of the DNA repair enzymes: ERCC-2, DNA polymerase beta, or topoisomerase I. There was also no difference in the levels of ERCC-1 protein between melphalan sensitive and resistant B-CLL lymphocytes. Analysis of genes involved in nitrogen mustard detoxification revealed that metallothionein was weakly expressed, while transcripts encoding glutathione-S-transferase alpha were undetectable. Thus, it is unlikely either of these proteins plays a role in the resistance. The results of the cytotoxicity assay validate the use of B-CLL as a model to study nitrogen mustard resistance. This model allows us to perform in vitro studies using a tumor which develops resistance in vivo. The results of this study suggest that nucleotide excision repair, as represented by ERCC-1 and ERCC-2, is not the limiting step in B-CLL nitrogen mustard resistance.

Aged↗
PubMed1982

Toxicity, interstrand cross-links and DNA fragmentation induced by 'activated' cyclophosphamide in yeast: comparative studies on 4-hydroperoxy-cyclophosphamide, its monofunctional analogon, acrolein, phosphoramide mustard, and nor-nitrogen mustard.

Activated cyclophosphamide (CP) is known to achieve its cytotoxic and alkylating capacity upon spontaneous hydrolytic breakdown of the oxazaphosphorine ring structure. Treatment of yeast cells with the chemically activated form of CP (4-hydroperoxy-CP, 4-OOH-CP) and with several potentially toxic cleavage products revealed that cytotoxicity is closely linked to the formation of DNA interstrand cross-links and to DNA fragmentation. While this holds true for 4-OOH-CP and its bifunctional alkylating breakdown products, phosphoramide mustard (PM) and nor-nitrogen mustard (NNM), equimolar concentrations of acrolein and the monofunctional analogon of activated CP were inactive. NNM, the ultimate cleavage product within the successive degradation of the oxazaphosphorine structure was five times more toxic than 4-OOH-CP, whereas the cytotoxic action of PM was only slightly enhanced. The high cytotoxicity of NNM was matched by its ability to induce DNA interstrand cross-links: at concentrations and treatment times producing equal cell killing, 4-OOH-CP and NNM produced the same extent of cross-linking and DNA fragmentation. Biochemical potency of NNM is in contrast to data found with the NBP colorimetric assay which suggest that NNM loses its alkylating activity at neutral pH. 4-OOH-CP and PM are much more stable than predicted from half-life measurements performed via the NBP colorimetric assay: they retain a considerable fraction of their cytotoxic and cross-linking activity in spite of a 12-h preincubation at pH 7 and 36 degrees C.

Acrolein↗
PubMed2003

The protective and therapeutic effects of zinc chloride and desferrioxamine on skin exposed to nitrogen mustard.

The nitrogen mustard (HN2), which contains chloroethyl groups, is a potent inhibitor of DNA synthesis and cell growth. It also has vesicant properties. Due to these damaging effects of HN2 on the skin, zinc chloride (ZnCl2) and desferrioxamine were used in the form of ointment for treatment and prevention of the histopathological destruction of skin of guinea pigs. According to results of the histopathological study, both ZnCl2 and desferrioxamine had therapeutic and protective effects for HN2-induced skin damage at moderate levels. Taking into consideration the alkylating effect of HN2 on the skin, our results suggest that ZnCl2 and desferrioxamine may be used in the prevention of nuclear damage and for handling the burns caused by the HN2.

Animals↗
PubMed1995

Influence of diltiazem on the ocular irritative response to nitrogen mustard.

Application of nitrogen mustard to the eye of rabbits causes an anterior segment irritation and a biphasic elevation of intraocular pressure. This intraocular pressure response is composed of an initial peak, produced by neuropeptides released by excited sensory nerves, and a second, slower rise due to prostaglandins. We studied the effect of diltiazem, a calcium antagonist that selectively blocks chemical excitation of sensory nerves, on the inflammatory response to nitrogen mustard. In adult rabbits, intraocular pressure was determined by pneumatonometry; pupil diameter and palpebral opening were measured with a ruler while conjunctival vasodilation, edema and secretion were scored in subjective units (0-8). Aqueous humor protein content was analysed at the end of the experiment. Bilateral application of 1% nitrogen mustard evoked within the first 6 hr an intraocular pressure elevation followed by ocular hypotony, miosis, palpebral closure, conjunctival vasodilation, edema and an elevation of aqueous proteins. Topical application of 10 mM diltiazem, prior to administration of nitrogen mustard elicited by itself a transient, small intraocular pressure increase and reduced significantly the acute intraocular pressure elevation and conjunctival vasodilation evoked by the irritant; delayed conjunctival edema and palpebral closure were also attenuated by 10 mM diltiazem. The decrease of miotic response and of aqueous humor protein content was not significant. Diltiazem at 2.8 mM was effective only in reducing significantly conjunctival edema and vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed2001

Chlorophyllin protects cells from the cytostatic and cytotoxic effects of quinacrine mustard but not of nitrogen mustard.

Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, is capable of inhibiting the mutagenic activity of many chemical compounds. Several mechanisms have been advanced to explain the antimutagenic activity of CHL, including its antioxidant properties and its ability to form complexes with mutagens. The present study was designed to reveal whether the heterocyclic aromatic nature of a potential mutagen is essential to its sensitivity to CHL. Toward this end, the inhibitory effect of CHL on two compounds of similar chemical reactivity (mustards), that either embodied an aromatic structure (quinacrine mustard; QM) or did not (nitrogen mustard; NM), were compared. Human leukemic HL-60 and breast carcinoma MCF-7 cells were treated with QM or NM in the absence or presence of various concentrations of CHL. Both QM and NM when administered for 1-2 h at micromolar concentrations exerted similar effects; both arrested cells in G2 phase of the cell cycle, induced apoptosis and reduced the clonogenicity of MCF-7 cells. The simultaneous addition of 0.22 M CHL to cultures receiving QM virtually abolished the QM-induced inhibition of cell growth and clonogenicity. In contrast, CHL had no effect on reducing the cytostatic or cytotoxic activity of NM. CHL alone, at a concentration of 0.22 M, had minimal effect on growth of HL-60 cells slightly perturbing their progression through G2. The results are consistent with the model that explains the inhibition of the activity of mutagens or antitumor drugs with aromatic structures by CHL as mediated by its ability to sequester these molecules within heterologous mutagen:CHL complexes that are maintained by stacking interactions. Therefore, excess of chlorophyll in the diet, by sequestering aromatic mutagens (or antitumor drugs with a heterocyclic structure, if taken orally), may inhibit their accessibility to cells, thereby reducing their activity.

Antimutagenic Agents↗
PubMed1990

[Immunomodulating effects of low doses of nitrogen mustard derivatives].

Chlormethine (Nitrogen mustard) in small doses proved to have immunopotentiating and anti-inflammatory activities. The influence of two nitrogen mustard derivatives : chlorambucil (1 or 10 micrograms/kg p.o.) and cyclophosphamide (0.03 or 0.3 mg/kg i.v.) as well as busulphan (0.5 or 5 micrograms/kg p.o.)--the agent of ++alkylating cytostatic group were investigated in rabbits. Whole blood count, the number of T and B lymphocytes, serum IgG level, phagocytic and microbicidal activities of neutrophils and the plasma level of free glucocorticoids were estimated. The drugs were used in the doses 10-100 times lower than cytostatic ones. Moreover, the ability of alkylating drugs to enhance or to suppress the changes evoked by lipopolysaccharide of E. coli in examined parameters was assessed. The results were compared with chlormethine data obtained previously. None of two nitrogen mustard derivatives (chlorambucil or cyclophosphamide) in the doses many times lower than cytostatic ones, exhibited an immunostimulating and adjuvant properties characteristic of chlormethine. Such properties did not demonstrate small doses of busulphan, another compound of alkylating drugs.

Adjuvants, Immunologic↗
PubMed2002

The role of DNA repair in nitrogen mustard drug resistance.

The nitrogen mustards are an important class of DNA cross-linking agents, which are utilized in the treatment of many types of cancer. Unfortunately, resistance often develops in the treatment of patients and the tumor either never responds to or becomes refractory to these agents. Resistance to the nitrogen mustards in murine and human tumor cells has been reported to be secondary to alterations in (i) the transport of these agents, (ii) their reactivity, (iii) apoptosis and (iv) altered DNA repair activity. In the present review, we will discuss the role of DNA repair in nitrogen mustard resistance in cancer. The nitrogen mustards' lethality is based on the induction of DNA interstrand cross-links (ICLs). Two DNA repair pathways are known to be involved in removal of ICLs: non-homologous DNA end-joining (NHEJ) and Rad51-related homologous recombinational repair (HRR). The reports discussed here lead us to hypothesize that low NHEJ activity defines a hypersensitive state, while high NHEJ activity, along with increased HRR activity, contributes to the resistant state in chronic lymphocytic leukemia. Studies on human epithelial tumor cell lines suggest that HRR rather than NHEJ plays a role in nitrogen mustard sensitivity.

Antineoplastic Agents, Alkylating↗