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PubMed1987

Glutathione and related enzymes in rat brain tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea and nitrogen mustard.

Reduced glutathione (GSH) and activities of several glutathione-related enzymes were measured in two 9L rat brain tumor cell lines with differing sensitivities to both 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and nitrogen mustard. GSH, measured by a specific high-performance liquid chromatographic method, was found to be approximately twice as high in 9L cells sensitive to BCNU but resistant to nitrogen mustard. The nitrogen mustard resistant cell line was also found to have 2.5-fold more bulk glutathione transferase activity and approximately 3-fold more gamma-glutamyl transpeptidase activity. Glutathione reductase activity, protein thiol, and total protein content were similar in the two cell lines. Pretreatment of 9L cells with 50 microM buthionine sulfoximine for 24 h to deplete GSH only slightly potentiated BCNU cytotoxicity in a clonogenic assay whereas that of nitrogen mustard was markedly potentiated in both cell lines. Similarly, buthionine sulfoximine pretreatment had little effect on the induction of sister chromatid exchanges by BCNU, but significantly increased the number of sister chromatid exchanges induced by nitrogen mustard in both cell lines. Depleting GSH also had no significant effect on the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea to 9L cells. Pretreatment of 9L cells with 1 mM GSH significantly protected against nitrogen mustard cytotoxicity. Moreover, nitrogen mustard incubated with GSH and glutathione transferase was 4-fold less cytotoxic than nitrogen mustard incubated with GSH alone. Incubation of BCNU with GSH alone or with glutathione transferase had no effect on BCNU cytotoxicity. These results indicate that elevated GSH and glutathione transferase activity is one mechanism of cellular resistance to nitrogen mustard in the 9L cell line, but it does not correlate with resistance to BCNU or other clinically important nitrosoureas.

Animals↗
PubMed2006

Molecular mechanism of nitrogen mustard induced leukocyte(s) chemotaxis.

Nitrogen mustard(s) (NM) are the primary chemotherapeutic agents (Chlorambucil, BSO) that are used in treating the B-cell chronic lymphocyte leukemia (B-CLL). It is known that NM imparts oxidative stress by inducing the reactive oxygen species (ROS) and reactive nitrogen species (RNS) production in B-lymphocytes of B-CLL. It is likely that these nitrogen mustards can cause the oxidative stress in the peripheral blood leukocytes (PBL) of B-CLL patients. It is possible that chronic exposure of PBL to NM would induce drug resistance in B-CLL patients. However, the precise molecular mechanism(s) by which NM affect the PBL are not known at present. Here, an effort is made to present plausible mechanisms by which chronic NM exposure could lead to increased PBL chemotaxis and vascular tissue damage in B-CLL patients The clinical implication of this phenomenon is most likely the unwanted organ dysfunction in B-CLL patients. Identification of viable therapeutic targets to attenuate the PBL activation during the NM therapy would be beneficial for the clinical remission of B-CLL.

Chemotaxis, Leukocyte↗
PubMed1994

Role of the cdc25C phosphatase in G2 arrest induced by nitrogen mustard.

G2 arrest induced by nitrogen mustard in human lymphoma CA46 cells is associated with a failure to activate hyperphosphorylated cdc2/cyclin B1 complexes. We investigated the possibility that this might be due to a suppression of cdc25C phosphatase activity. cdc25C from interphase cells migrated as a 54- to 57-kDa doublet in SDS gels and exhibited basal phosphatase activity. cdc25C from mitotic cells migrated as a 66-kDa hyperphosphorylated species and exhibited elevated phosphatase activity. cdc25C hyperphosphorylation and activation were mediated by cdc2, supporting the view of a cdc2-cdc25C autocatalytic feedback loop. Immunofluorescence and cell fractionation studies suggested cdc2-cdc25C interaction occurred within the cytoplasm. Cells arrested in G2 phase following nitrogen mustard treatment or cells arrested in S phase with aphidicolin failed to dephosphorylate and activate cdc2, and this correlated with failure to convert cdc25C into the most active hyperphosphorylated species. Our findings suggest that checkpoints guarding against mitotic entry in the presence of unreplicated or damaged DNA suppress formation of the cdc2-cdc25C autocatalytic feedback loop that normally brings about rapid activation of cdc2.

Aphidicolin↗
PubMed1975

The alkylation of hemoglobin S by nitrogen mustard. High resolution proton nuclear magnetic resonance studies.

Sickle cell hemoglobin (Hb S) treated with nitrogen mustard (bis(beta-chloroethyl)methylamine hydrochloride) gives two reaction products, one labile and one stable. After dialysis against buffer solution, the remaining stable product is found to inhibit the polymerization of deoxyhemoglobin S. High resolution proton nuclear magnetic resonance has been used to study the structure and function of this stable product and to investigate the nature of the binding sites of nitrogen mustard to the hemoglobin molecule. The NMR results suggest that the nitrogen mustard treatment of Hb S does not alter the heme environment or the subunit interfaces of the hemoglobin molecule. Moreover, the NMR spectra have also shown that the nitrogen mustard reacts with the beta2 histidines of the hemoglobin molecule and have suggested that several other surface amino acid residues of the hemoglobin molecule are also affected by the nitrogen mustard alkylation. These NMR findings are in good agreement with the data obtained from biochemical studies of nitrogen mustard-treated Hb S. The NMR spectra also indicate that nornitrogen mustard (which is also effective in inhibiting sickling) binds with the hemoglobin molecule in a manner identical with nitrogen mustard. Sulfur mustard, on the other hand, produces no observable changes in the aromatic proton resonances, which is consistent with the fact that it does not inhibit the polymerization of deoxy-Hb S.

Adult↗
PubMed1995

Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance.

Acquired resistance is a limiting factor in chemotherapy. We have employed nitrogen mustard resistant B-cell chronic lymphocytic leukemia (B-CLL) as a clinically relevant model to study this phenomenon. Resistance in B-CLL is associated with enhanced repair of nitrogen mustard crosslinks. In order to identify the repair pathway responsible for nitrogen mustard resistance, lymphocytes were screened for cross-resistance to a variety of DNA damaging agents. The MTT assay was used to measure the resistance of B-CLL lymphocytes to various DNA damaging agents, including nitrogen mustards, UV light, methyl methanesulfonate, and mitomycin C. We have shown that B lymphocytes from patients with nitrogen mustard resistant chronic lymphocytic leukemia reflect their clinical status. This assay allows us to classify lymphocytes as nitrogen mustard sensitive or resistant, based on in vitro observations. The resistant population was 5.6 and 4.1 fold more resistant to the nitrogen mustard analogs, chlorambucil and melphalan, respectively. Resistant lymphocytes displayed no increased resistance to either methyl methanesulfonate or UV light, indicating that neither classical base nor nucleotide excision repair is rate-limiting in resistance. Resistant lymphocytes were 6.0 and 2.2 fold more resistant to mitomycin C and cis-diamminedichloroplatinum (II), respectively, suggesting enhanced crosslink repair. Neither glutathione nor glutathione S-transferase levels correlated with resistance. The development of nitrogen mustard drug resistance in B-CLL appears to be associated with cross-resistance to other bifunctional alkylating agents which produce interstrand crosslinks. Our results indicate that resistance to nitrogen mustards in chronic lymphocytic leukemia is associated with enhanced repair of DNA crosslinks which may involve a recombination dependent system. This model should prove very useful in the elucidation of the molecular mechanisms of crosslink repair.

B-Lymphocytes↗
PubMed1997

Comparison of nitrogen mustard, cytarabine and dacarbazine as pleural sclerosing agents in rabbits.

We have previously shown that the intrapleural injection of mitozantrone but not bleomycin resulted in pleural fibrosis. Mechlorethamine hydrochloride (nitrogen mustard) was used extensively in the past to control malignant effusions, with relatively good success. The objective of this study was to determine if the intrapleural injection of nitrogen mustard would produce pleural sclerosis in our experimental model in rabbits. We therefore evaluated sclerosing capabilities of nitrogen mustard as well as those of cytarabine and dacarbazine. Nitrogen mustard (0.4 and 0.8 mg x kg(-1)), cytarabine (3, 6 and 20 mg x kg(-1)) and dacarbazine (4, 8 and 20 mg x kg(-1)) were instilled intrapleurally into anaesthetized rabbits. Twenty eight days after the instillation, the animals were killed, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of 0.8 mg x kg(-1) nitrogen mustard was effective in creating pleural fibrosis, either grossly or microscopically. The mean degree (scale 0-4) of gross pleurodesis in the rabbits that received 0.8 mg x kg(-1) nitrogen mustard was 3.2+/-1.0 and the mean degree of microscopic pleural fibrosis was 3.5+/-0.8. The intrapleural injection of 0.4 mg x kg(-1) nitrogen mustard and the different doses of cytarabine (3, 6 and 20 mg x kg(-1)) and dacarbazine (4, 8 and 20 mg x kg(-1)) were ineffective in producing pleurodesis. From this study, we conclude that the intrapleural injection of 0.8 mg x kg(-1) of nitrogen mustard produces clinically significant pleurodesis in rabbits. Consideration should be given to future clinical studies utilizing 0.6-0.8 mg x kg(-1) nitrogen mustard intrapleurally for the treatment of malignant pleural effusion.

Animals↗
PubMed1994

Synthesis and DNA-sequence selectivity of a series of mono- and difunctional 9-aminoacridine nitrogen mustards.

The aim of this work was to identify nitrogen mustards that would react selectively with DNA, particularly in G-rich regions. A series of mono- and difunctional nitrogen mustards was synthesized in which the (2-chloroethyl)amino functions were connected to the N9 of 9-aminoacridine by way of a spacer chain consisting of two to six methylene units. The length of the spacer chain connecting the alkylating and putative DNA-intercalating groups was found to affect the preference for the alkylation of different guanine-N7 positions in a DNA sequence. All of the compounds reacted preferentially at G's that are followed by G as do most other types of nitrogen mustards, but the degree of selectivity was greater. The compounds reacted at much lower concentrations than were required for comparable reaction by mechlorethamine (HN2), consistent with initial noncovalent binding to DNA prior to guanine-N7 alkylation. The degree of DNA-sequence selectivity increased as the spacer-chain length decreased below four methylene units. Most strikingly, long spacer compounds reacted strongly at 5'-GT-3' sequences, whereas this reaction was almost completely suppressed when the spacer length was reduced to two or three methylenes. Mono- and difunctional compounds of a given spacer length showed no consistent difference in DNA-sequence preference.

Acridines↗
PubMed1981

Human monocytes and lymphocytes differ in the rate of DNA repair synthesis and viability after exposure to nitrogen mustard.

Unscheduled DNA synthesis was studied in human lymphocytes and monocytes after treatment with nitrogen mustard, methyl-methane-sulphonate and ultraviolet irradiation. The unscheduled DNA synthesis was about 4 times higher in monocytes than in lymphocytes after treatment with nitrogen mustard. Treatment with methyl-methane-sulphonate or ultraviolet irradiation confirmed the higher capacity for unscheduled DNA synthesis in the monocytes. When Ficoll-Isopaque-isolated mononuclear cells were exposed to various doses of nitrogen mustard and incubated for different periods, a dose- and time-dependent increase in trypan blue uptake was found. Furthermore, a corresponding dose- and time-dependent decrease was noted in 3H-uridine incorporation. Since trypan blue uptake will not enable differentiation between monocytes and lymphocytes appearing as a mixed cell population, 3H-uridine flash labeling index was studied after exposure to nitrogen mustard. There was a dose- and time-dependent decrease in 3H-uridine labeling index, suggesting a correlation between the absence of 3H-uridine incorporation and increase in trypan blue uptake. When compared to monocytes, the lymphocytes were more affected in this respect after exposure to nitrogen mustard. The possibility that differences in cytotoxic effect may be related to DNA repair mechanisms is discussed.

DNA↗
PubMed1992

Influence of DNA repair defects (rad1, rad52) on nitrogen mustard mutagenesis in yeast.

Nitrogen mustard (HN2) mutagenesis of a plasmid-borne copy of the Saccharomyces cerevisiae SUP4-o gene was examined in a repair-proficient yeast strain and isogenic derivatives defective for excision (rad1) or DNA double-strand break (rad52) repair. The excision repair deficiency sensitized the cells to killing by HN2 and abolished mutation induction. Inactivation of RAD52 had no influence on the lethality of HN2 treatment but diminished the induced mutation frequency by 50% at all doses tested. DNA sequence analysis of HN2-induced SUP4-o mutations suggested that RAD52 contributed to the production of basepair substitutions at G.C sites. The rad52 defect appeared to alter the distribution of G.C-->A.T transitions in SUP4-o relative to the distribution for the wild-type strain. This difference did not seem to be due to an effect of RAD52 on the relative fractions of HN2-induced transitions at localized (flanked by A.T pairs) or contiguous (flanked by at least one G.C pair) G.C sites but instead to an influence on the strand specificity of HN2 mutagenesis. In the repair-proficient strain, the transitions showed a small bias for sites having the guanine on the transcribed strand and this preference was eliminated by inactivation of RAD52.

Base Composition↗
PubMed2003

Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience.

OBJECTIVE: To evaluate and update the response and survival outcomes and toxic effects in patients treated with topical nitrogen mustard (mechlorethamine hydrochloride) as primary therapy. DESIGN: A single-center, retrospective cohort analysis. SETTING: Academic referral center for cutaneous lymphoma. PATIENTS: A total of 203 patients with mycosis fungoides (clinical stages I-III) treated with topical nitrogen mustard as initial therapy. MAIN OUTCOME MEASURES: Long-term actuarial survival, freedom-from-relapse, and freedom-from-progression results as calculated by the Kaplan-Meier method. RESULTS: The overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve complete response was 12 months (T1, 10 months; T2, 19 months), and the median time to relapse was 12 months. The duration of complete response increased with longer maintenance therapy; however, after completion of therapy, the response duration or relapse rate was similar regardless of maintenance regimen. Patients with T1 disease had better response and survival outcomes than those with T2 disease, with overall and complete response rates in T1 of 93% and 65%, respectively, and in T2, 72% and 34%, respectively. A similar clinical response was seen for patients with stage IIA vs IB. Sixty-eight percent of 203 patients received only topical nitrogen mustard therapy throughout their follow-up course, including most of the patients who achieved an initial complete response. The clinical response to topical nitrogen mustard as salvage therapy was similar to initial response rates. The efficacy results were similar in patients treated with aqueous vs ointment preparations. Freedom-from-progression rates in T1 disease (no progression to higher T classification or worse clinical stage) at 5 and 10 years were 92% and 85%, respectively, and in T2, 83% at 5 and 10 years. Fewer than 10% of patients experienced contact hypersensitivity reactions when topical nitrogen mustard was used as an ointment preparation. Only 8 patients (4%) developed secondary cutaneous malignancy, none attributable to topical nitrogen mustard monotherapy. Pediatric patients experienced no significant toxic effects with topical nitrogen mustard therapy. CONCLUSIONS: Topical nitrogen mustard remains an effective primary initial or salvage therapy in mycosis fungoides for patients with T1 and T2 disease. Long-term follow-up results confirm its safety.

Administration, Topical↗
PubMed1992

DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards is preserved in intact cells.

Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct sequence preference. It is not clear however to what extent the observed DNA sequence preferences are preserved in intact cells. The highly reiterated sequence of human alpha DNA has been used to determine the sites of guanine-N7 alkylation following treatment of cells with three nitrogen mustards, mechlorethamine, uracil mustard and quinacrine mustard, known to react in isolated DNA with distinctly different sequence preferences. Alpha DNA from drug treated cells was extracted, purified, end-labeled, and a 296 base pair, singly end-labelled, fragment isolated. Following the quantitative conversion of alkylation sites to strand breaks the fragments were separated on DNA sequencing gels. Clear differences were observed between the alkylation patterns of the three compounds, and the selectivities were qualitatively similar to those predicted and observed in the same sequence alkylated in vitro. In particular the unique preferences of uracil and quinacrine mustards for 5'-PyGC-3' and 5'-GT/GPu-3' sequences, respectively, were preserved in intact cells suggesting that the pattern of sequence dependent reactivity is not grossly affected by the nuclear milieu.

Alkylation↗
PubMed2004

Morphological and immunohistochemical changes on rat skin exposed to nitrogen mustard.

OBJECTIVE: The aim of this study was to understand the mechanism of nitrogen mustard on skin. METHODS: Nitrogen mustard was applied on ventral skin of 30 rats. Sequential biopsies were taken during the postexposure period. Slides were stained with hematoxylin-eosin and keratin PAN and high molecular weight cytokeratin and keratin 5. RESULTS: The earliest findings are minimal polymorphonuclear leukocytes extravasation and edema. Heavy inflammation with formation of vesicles and bulla were present at 24 hours. At 6 hours, the upper epidermal cells showed weak staining with high molecular weight cytokeratin and keratin PAN. At 24 and 48 hours, only patchy areas of staining with high molecular weight cytokeratin and keratin 5 were present. CONCLUSION: One of the major mechanisms of injury by nitrogen mustard may be the disruption of cytoskeletal filament network.

Animals↗
PubMed1981

Immunochemistry of conjugates prepared from serum albumins and acridine nitrogen mustards (ICR mutagens).

Antibodies elicited in rabbits by immunization with conjugates prepared from serum albumins and nitrogen mustard derivatives of quinacrine (atebrin) were found to have strong binding sites complementary to the quinacrine hapten. The characteristic absorption spectrum of quinacrine made possible accurate determinations of the antigen-antibody composition of the serological precipitates. Conclusive evidence that such antibodies, in addition to reacting with the quinacrine component of heterologous protein test conjugates, bind quinacrine itself, as well as closely related acridine haptens, was provided by quantitative inhibition studies. Atebrin and the hydroxy precursors of several heterocyclic nitrogen mustards caused more than a 50% inhibition of the antigen-antibody reactions. The antibodies elicited by the quinacrine-protein conjugates in ascites tumor-bearing mice substantially neutralized the antitumor effectiveness of the low dosages (0.5 to 2.0 mumol/kg) of the acridine nitrogen mustards that were required for a demonstration of chemotherapeutic activity. In contrast, nitrogen mustard, which has no quinacrine moiety, was not affected. Immunization with unaltered serum albumin had no influence on the activity of the acridine nitrogen mustards. Quantitative in vitro inhibition studies allowed satisfactory predictions in vivo immunological reactivity.

Animals↗
PubMed2003

Management with topical nitrogen mustard in mycosis fungoides.

Topical nitrogen mustard (mechlorethamine, NM) has been used as primary therapy for management of patients with mycosis fungoides (MF) since the 1950s. Many investigators have demonstrated the efficacy of topical NM in patch and/or plaque disease of MF. Updated results from Stanford also confirm the clinical efficacy. The complete response (CR) rates reported are 76-80% for patients with limited patch/plaque (stage IA), and 35-68% for those with generalized patch/plaque (stage IB) disease. Topical NM can be used as an aqueous (water) or ointment-based preparation. The efficacy results are similar in patients who were treated with aqueous versus ointment preparations. Maintenance regimens used are variable, but there is no data to suggest that a longer maintenance duration results in greater potential for long-term remission. Most patients who achieve initial CR with topical NM tend to require NM-only for disease management. Topical NM is equally effective when used as salvage therapy with disease relapse. The most common toxicity of topical NM therapy is contact irritant or allergic reaction. The potential for allergic reaction is significantly reduced (< 10%) when NM is used as an ointment preparation. The potential for secondary skin cancer development is increased in patients who have used multiple sequential topical skin-damaging therapies or NM in the genital skin, but not in patients who have used NM as monotherapy (avoiding genital skin application). Topical NM is used safely in pediatric patients and there is no evidence of any clinically significant systemic absorption of topically applied NM.

Administration, Topical↗
PubMed2003

Topical nitrogen mustard ointment with occlusion for Langerhans' cell histiocytosis of the scalp.

BACKGROUND: Topical nitrogen mustard solution has been used as an effective alternative to corticosteroids for the treatment of cutaneous eruptions of Langerhans' cell histiocytosis (LCH). When used as an ointment under occlusion, nitrogen mustard may still be effective and possess less risk of unwanted side effects. METHODS: A patient with scalp LCH was treated topically with nitrogen mustard ointment 0.01% under occlusion. RESULTS: The lesions cleared in 3 weeks without irritation. CONCLUSION: Topical nitrogen mustard ointment 0.01% under occlusion is a well-tolerated, non-irritating treatment for scalp LCH.

Administration, Cutaneous↗
PubMed2000

Efficient protection of human bronchial epithelial cells against sulfur and nitrogen mustard cytotoxicity using drug combinations.

The aim of this study was to test the efficacy of several candidate molecules against sulfur mustard (SM) and nitrogen mustard (HN2) using a human bronchial-epithelial cell line (16HBE14o-). Candidate molecules were chosen on the basis of the known cytotoxicity mechanisms of mustards or their efficacy previously observed on other cellular models. It included the sulfhydryl-containing molecules N-acetyl-cysteine (NAC) and WR-1065, the nucleophile hexamethylenetetramine (HMT), the energy-level stabilizer niacinamide (NC), the antioxidant dimethylthiourea (DMTU), L-arginine analogues such as L-thiocitrulline (L-TC) and L-nitroarginine methyl ester (L-NAME), and the anti-gelatinase doxycycline (DOX). Their efficacy was determined using 2-(4-[3-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2Htetrazolium (WST-1) reduction by viable cells 24 h after initial exposure to 100 microM HN2 or SM. On individual immediate cotreatment, some molecules exhibited selective protection against only one mustard, such as DMTU and WR-1065 against HN2 and DOX against SM, whereas NAC and L-TC were effective against both SM and HN2 cytotoxicity. However, as the level of protection against SM was always weak compared to HN2, several combinations were investigated against SM to improve the protection. The effective combinations (L-TC + DOX, NAC + DOX, NAC + DMTU, NAC + HMT, NC + DOX) combined agents, reducing the bioavailability of the mustard with compounds possibly acting on the consequences of alkylation. One of these combinations, NAC + DOX, appeared to be the most interesting, as these agents are already used in human therapy. It exhibited good efficacy in delayed cotreatment (up to 90 min) against SM.

Acetylcysteine↗
PubMed1969

X-rays and nitrogen mustard: independent action in Chinese hamster cells.

We have studied the combined effects of X-irradiation and nitrogen mustard treatment on the colony-forming ability of Chinese hamster cells. In contrast to X-irradiation, nitrogen mustard acting by itself yields an exponential dose-effect relationship. Moreover, whether delivered in immediate sequence or after varying intervals, nitrogen mustard treatment does not affect radiation survival and vice versa. These results, plus the lack of any indication of the repair of sublethal nitrogen mustard damage, are consistent with independent but different modes of action at the same site(s), or action at different sites.

Animals↗