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PubMed1991

Determination of reactive nitrogen mustard anticancer drugs in plasma by high-performance liquid chromatography using derivatization.

A high-performance liquid chromatography (HPLC) method is described for the determination of reactive nitrogen mustard anticancer drugs in plasma after derivatization with diethyl-dithiocarbamic acid (DDTC). Three compounds were studied: two reactive species (mechlorethamine (HN2) and galactose 6-mustard (G-6-M] and a less reactive species (melphalan (L-PAM] included for validation experiments. Mass and NMR spectrometry confirmed that one molecule of DDTC reacts with each arm of the mustard, displacing a chlorine atom to form a stable disubstituted adduct. With the reactive mustards a 30-min incubation at 37 degrees C is recommended for greater than 90% derivatization efficiency. Gradient elution was employed to analyze all three compounds using the same conditions with a microBondapak C18 10-microns particle size column (30 cm by 3.8 mm i.d.). The retention time (tR) of HN2-DDTC2 was 13.1 min +/- 1.5% within day CV; tR of L-PAM was 7.6 min and L-PAM-DDTC2 was 14.6 min +/- 0.8% CV. G-6-M-DDTC2 yielded a double peak, tR = 10.7 min and 10.9 min +/- 2.9% CV. The limit of detection on column was 0.5 ng for HN2, 1 ng for L-PAM, and 5 ng for G-6-M. A solid-phase sample preparation technique using "Bond Elut" phenyl is described that extracts from plasma G-6-M-DDTC2 with greater than 74% efficiency and HN2-DDTC2 with greater than 90% efficiency. When the drugs were derivatized in plasma, recovery remained high for G-6-M (greater than 84%) but dropped to 50% for HN2.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1998

Effect of nucleosome structure on DNA interstrand cross-linking reactions.

Antitumor agents of the nitrogen mustard family and mitomycin C form interstrand cross-links in duplex DNA. To provide information about the cellular mechanism by which these compounds exert their cytotoxic effects, we examined cross-linking of a nucleosomal core particle formed on a fragment of the 5S RNA gene of Xenopus borealis. For the mustards mechlorethamine, chlorambucil, and melphalan, both sites of monoalkylation and interstrand cross-linking were similar in nucleosomal and free DNA. Some small (two- to three- fold) differences in intensity of cross-linking at some sites were apparent. However, these differences did not appear to correlate with rotational or translational positioning. For mitomycin C, cross-linking was inhibited five- to ten-fold at the nucleosomal dyad and showed attenuation of inhibition toward the ends. Furthermore, rotational positioning also appeared to be a factor, with sites facing inward in the nucleosome less accessible for mitomycin cross-linking. None of these agents demonstrated the 10-base pair periodicity exhibited by hydroxyl radical cleavage of nucleosomal DNA.

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↗
PubMed1996

Synthesis and antitumor evaluation of a highly potent cytotoxic DNA cross-linking polyamine analogue, 1,12-diaziridinyl-4,9-diazadodecane.

A diaziridinylspermine analogue, 1,12-diaziridinyl-4,9-diazadodecane (NSC-667005), was synthesized as a bisalkylating agent with a polyamine backbone. DNA cross-linking was detected in the reaction of linearized pBR322 DNA with 1,12-diaziridinyl-4,9-diazadodecane at concentrations comparable with that required for cross-linking by two nitrogen mustard drugs, mechlorethamine and melphalan. A significant increase in life span of female CD2F1 mice bearing L1210 murine leukemia was observed after intravenous administration of 1,12-diaziridinyl-4,9-diazadodecane in doses of less than 2.7 mg/kg, given on days 1, 5, and 9 of treatment.

Animals↗
PubMed1995

Alkylation of DNA by the nitrogen mustard bis(2-chloroethyl)methylamine.

Alkylation of DNA by the nitrogen mustard bis(2-chloroethyl)methylamine (mechlorethamine; HN2) gave four principal products, derived by mono-alkylation of guanine at N-7 and adenine at N-3 and by cross-linking of guanine to guanine or guanine to adenine at these positions. These products were isolated by hydrolysis from DNA at neutral pH, followed by ion-exchange chromatography on SP-Sephadex and reversed phase chromatography on ODS. They were characterized by identification with products from the reaction of nitrogen mustard with adenine or deoxyguanylic acid, and by their UV, mass, and proton magnetic resonance spectra.

Alkylation↗
PubMed1997

MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children.

Infants and young children who have brain tumors have a poor rate of survival and high treatment associated morbidity. A trial of mechlorethamine, vincristine (oncovin), procarbazine, and prednisone (MOPP) was performed to test the hypothesis that replacing radiotherapy with chemotherapy would improve survival and decrease long term morbidity of infants who have brain tumors. Between 1976 and 1988, 17 consecutive children less than 36 months old when diagnosed with medulloblastoma or ependymoma were treated with MOPP chemotherapy as primary therapy following surgical excision or biopsy of the tumor. Radiotherapy was reserved for recurrent disease. Ten of 17 children have survived without evidence of disease: medulloblastoma eight of 12 with median survival time of 10.6 years (range, 6.2 to 15.2 yrs); and ependymoma, 2 of 5 (at 13.0 and 16.0 yrs). Four of the 10 children with medulloblastoma and ependymoma who relapsed are now disease free at 7.5, 11.7, 12.2 and 13.5 yrs post relapse after receiving salvage therapy with cisplatin (n = 1) or irradiation (n = 3). All relapses occurred within 26 months of diagnosis. Data on growth demonstrated height less than the 5th percentile in all children who received cranial irradiation compared to 25 to 95th percentile for nonirradiated children. Intellectual ability for the group who did not require radiation was within normal range (mean IQ 100.1) and stable across annual assessments. Those who required radiation had lower IOs which continued to decline over time (mean IQ 85 at mean age of 5.8 years, declining to 63 at 10 years). In young children with brain tumors, primary chemotherapy with MOPP, omitting radiotherapy, provides improved neurodevelopmental outcome and survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1979

Ablation of murine jejunal crypts by alkylating agents.

The gut microcolony assay has been used to measure damage to intestinal crypts by single and split doses of 3 alkylating agents: mechlorethamine hydrochloride (HN2), bis-chloroethyl-nitrosourea (BCNU) and isopropyl methane sulphonate (IMS). The single-dose survival curves for whole crypts were distinguished by extrapolation numbers (3.0, 176 and 1.5 respectively) that were lower than most previously published values for assay by irradiation. Significant sparing of crypts occurred when doses of HN2 or BCNU, but not IMS, were given in 2 equal fractions separated by more than 2 h. Deduced D0 values for those cells from which crypts regenerate were 1.9 mg/kg HN2, 19 mg/kg BCNU and 487 mg/kg IMS.

Alkylating Agents↗
PubMed1984

Death of intestinal crypts and of their constituent cells after treatment by chemotherapeutic drugs.

The number and spatial distribution of necrotic cells in the jejunal crypts of mice, has been measured after treatment by each of 6 cytotoxic drugs. At the LD10/8 day dose of each drug, the majority of necrotic cells were found below position 9 and numbers per crypt were similar for all drugs (approximately 8). These findings resemble those for radiation. However, major differences between agents were found in the calculated numbers of the microcolony-forming units (MFU) that determine overall crypt survival or ablation after high doses of cytotoxic agent. Numbers of MFU as assayed by radiation were approximately 80 per crypt, but only 2 when assayed by mechlorethamine hydrochloride, adriamycin and 5-fluorouracil, and 7 using BCNU. No crypts were destroyed by either cyclophosphamide or actinomycin D, despite the appearance of numerous necrotic cells in the lower part of the crypt. We conclude that in drug-treated intestine, necrotic cells may arise from a non-MFU compartment and the incidence and distributions of such cells are likely to be poor indicators of the response of the MFU.

Animals↗
PubMed1999

Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis.

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.

Animals↗
PubMed2002

Fifteen-year secondary leukaemia risk observed in 761 patients with Hodgkin's disease prospectively treated by MOPP or ABVD chemotherapy plus high-dose irradiation.

Between 1972 and 1988, 869 adult patients received MOPP (mechlorethamine, vincristine, procarbazine and prednisone; 462 patients) or ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine; 373 patients) and subsequent high-dose irradiation for Hodgkin's disease. Nine patients developed a leukaemia after MOPP and four after ABVD; 11 patients were diagnosed as acute non-lymphoblastic leukaemia (ANLL) and two as acute lymphoblastic leukaemia (ALL). Both cases of ALL were observed after ABVD and were associated with a 11q23 translocation. The 15-year actuarial risk of secondary leukaemia was 2.4% for the whole group of patients, 3.4% after MOPP and 1.3% after ABVD. For the MOPP subgroup, the risk of leukaemia was significantly associated with the extent of irradiation: 2.4% for limited irradiation and 13.9% for extended irradiation (P < 0.001). For the ABVD subgroup, this risk remained low (1.3%) whatever the type of irradiation. Concerning ANLL, the MOPP regimen was significantly associated with a higher risk: 3.4% versus 0.7% for ABVD (P<or=0.05). The 15-year risk of ALL was 0.6 after ABVD regimen. This study demonstrated that ABVD induced less ANLL than MOPP. However, a low risk of ALL with a 11q23 translocation related to topoisomerase II inhibitors was observed.

Actuarial Analysis↗
PubMed1985

[Chemotherapy of advanced lymphogranulomatosis. Results of MOPP/COPP treatment at the West German Tumor Center, Essen].

Between 1968 and 1979, a total of 271 patients with advanced Hodgkin's disease received as first systemic chemotherapy MOPP (mechlorethamine [nitrogen mustard], oncovin [vincristine], procarbazine and prednisone) or COPP (as above, but cyclophosphamide instead of nitrogen mustard). In 162 of the 271 patients (60%) full remission was achieved. Demonstration of systemic signs, bioptically confirmed bone-marrow infiltration and suboptimal cytostatic dosage correlated significantly with a lower full-remission rate. A significant trend towards a lower remission rate was demonstrated for stage IV disease, in patients with lymphocyte-poor or unclassified Hodgkin's disease and in those older than 30 years. A five-year recurrence-free period was achieved in 75.5% of patients: stage of the disease and bone-marrow infiltration had a clear influence on recurrence-free survival rate. The results show that 50% of patients with advanced Hodgkin's disease can be cured by chemotherapy.

Adult↗
PubMed1978

Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin's disease.

We studied 19 Ugandan boys with Hodgkin's disease who had been treated with mechlorethamine, vincristine, procarbazine and prednisone and who survived at least two years to assess testicular germ-cell depletion in pubescent boys on combination chemotherapy, as had previously been demonstrated in sexually mature men. Nine of 13 pubertal boys (ages 11 to 16) had moderate to severe gynecomastia and germinal aplasia, a 10-fold increase in mean (+/- S.D.) serum follicle-stimulating hormone (34.8 +/- 20.5 mlU per milliliter), a threefold increase in mean luteinizing hormone (17.8 +/- 9.8 mlU per milliliter) and reduced serum testosterone levels. Gynecomastia was not associated with an increase in either serum estradiol or prolactin concentrations. By contrast, six prepubertal boys (three to 10 years of age), similarly treated, showed no change in serum gonadotropins, and gynecomastia did not develop. The data confirm germ-cell depletion after combination chemotherapy and indicate further that Leydig-cell dysfunction, manifested by gynecomastia, may be a consequence of treatment in adolescent boys.

Adolescent↗
PubMed1982

Alternating drug combinations in the treatment of advanced Hodgkin's disease.

Of 75 consecutive patients with Stage IV Hodgkin's disease, we assigned 38 to receive MOPP alone (mechlorethamine, vincristine, procarbazine, and prednisone) and 37 to receive MOPP alternating monthly with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - a combination of drugs not cross-resistant with MOPP. Complete remission was documented in 71 percent of the patients receiving MOPP alone and in 92 per cent of those receiving the alternating regimen (P = 0.02). At five years, there was no progression of disease in 37 per cent of the MOPP group and in 70 per cent of the MOPP-plus-ABVD group (P less than 0.0001). After chemotherapy, the median relapse-free survival period was 20 months in the MOPP group and over 31 months in the MOPP-plus-ABVD group (P less than 0.01). Five-year survival with no evidence of disease was 84 per cent in patients given MOPP and ABVD and 54 per cent in those given MOPP alone (P less than 0.005). We conclude than alternating non-cross-resistant combinations appear promising in the management of advanced Hodgkin's disease and are worthy of trial in other malignant diseases.

Adult↗
PubMed1992

Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.

BACKGROUND AND METHODS: MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkin's disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkin's disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen. RESULTS: Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose. CONCLUSIONS: In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Adult↗
PubMed2003

Involved-field radiotherapy for advanced Hodgkin's lymphoma.

BACKGROUND: The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin's lymphoma is controversial. METHODS: We randomly assigned patients with previously untreated stage III or IV Hodgkin's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP-ABV) to receive either no further treatment or involved-field radiotherapy. Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites. Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. RESULTS: Of 739 patients, 421 had a complete remission; 161 of these patients were assigned to no further treatment, and 172 to involved-field radiotherapy. The median follow-up was 79 months. The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that received involved-field radiotherapy (P=0.35). The five-year overall survival rates were 91 and 85 percent, respectively (P=0.07). Among the 250 patients in partial remission after chemotherapy, the five-year event-free and overall survival rates were 79 and 87 percent, respectively. CONCLUSIONS: Involved-field radiotherapy did not improve the outcome in patients with advanced-stage Hodgkin's lymphoma who had a complete remission after MOPP-ABV chemotherapy. Radiotherapy may benefit patients with a partial response after chemotherapy.

Adolescent↗
PubMed1980

Use of an indicator sequence of human DNA to study DNA damage by methylbis(2-chloroethyl)amine.

A highly reiterated sequence of human DNA was used to determine the sites of modification of DNA caused by the anti-tumor drug methylbis(2-chloroethyl)amine (HN2, mechlorethamine, nitrogen mustard) upon treatment of cells in culture and of purified DNA. The lengths of the breakage products of the DNA treated with HN2 were compared to the lengths of DNA scission products produced by chemical reactions used for DNA sequence determination. HN2 was found to create alkali-labile lesions at positions of guanine. The distribution of the guanine modifications was the same for DNA extracted from cells treated with HN2 and for purified DNA treated with HN2. However, the extent of damage was at least 2-fold greater when purified DNA was used as the substrate. Several nitrogen mustard analogues also produced alkali-labile lesions at positions of guanine.

Alkylating Agents↗
PubMed1985

Alkylating agent resistance: in vitro studies with human cell lines.

Development of in vitro resistance to HN2 (also called mustargen or mechlorethamine hydrochloride), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cisplatin [cis-diamminedichloroplatinum(II)] was achieved in two human cell lines, the Raji/Burkitt lymphoma and a squamous cell carcinoma of the tongue. A 10- to 20-fold increase in resistance relative to the parental line was achieved in 3-4 months of continuous selection pressure. At this time, further increase in selection pressure resulted in cell death, while removal of drug led to rapid loss of resistance. However, by holding selection pressure constant over 8-12 months, semistable clones ranging in resistance up to 8- to 12-fold were obtained. The half-life for resistance loss upon removal of drug was 2-3 months. In the presence of intermittent low concentrations of the alkylating agent, resistance has been maintained in excess of 9 months. With one exception, the growth kinetics of the resistant clones were slightly slower than those of the parental lines. Cross-resistance studies were performed against HN2, BCNU, cisplatin, phenylalanine mustard, and hydroperoxycyclophosphamide. There was, in general, a lack of cross-resistance. We conclude that stable resistance to alkylating agents is produced with difficulty. We propose that these semistable cloned human tumor lines represent clinically relevant models for the study of alkylating agent resistance and that the cross-resistance patterns among these cells have important therapeutic and mechanistic implications.

Alkylating Agents↗
PubMed1968

The induction of graft versus host disease in mice treated with cyclophosphamide.

In these studies adult mice treated with cyclophosphamide and foreign immunologically competent cells developed a graft versus host disease which outwardly resembled that encountered in other experimental systems. Progressively larger doses of cyclophosphamide produced an increasingly severe disease whereas comparable doses of mechlorethamine were ineffective. Increasingly larger cell inocula from parental, allogeneic, and xenogeneic donors resulted in a correspondingly more severe disease. Nucleated cells obtained from the peripheral blood were found to be the most potent inducers of this syndrome, while cells from the spleen, bone marrow, and thymus displayed lesser degrees of reactivity in that order. No such graft versus host disease occurred in mice given saline, lysed, or heat-killed cells in place of viable foreign cells. Neither did the disorder develop when comparable inocula of isogeneic cells were used.

Animals↗