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PubMed1975

Microsomal monooxygenation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Synthesis and identification of cis and trans monohydroxylated products.

Liver microsomal hydroxylation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was shown to occur on the cyclohexyl ring at positions 3 and 4. Four metabolites were isolated by selective solvent extraction and purifed by high-pressure liquid chromatography. cis-4-, trans-4-, cis-3-, and trans-3-OH derivatives of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea were synthesized and their chromatographic, mass spectral, and nuclear magnetic resonance characteristics matched those of the metabolites. The position of ring hydroxylation and the identity of each geometric isomer were established by nuclear magnetic resonance using a shift reagent in conjunction with spin decoupling techniques. Microsomes from rats pretreated with phenobarbital showed a sixfold increase in hydroxylation rate (19.5 vs. 3.3 nmol per mg per min). The induction was quite selective for cis-4 hydroxylation (19-fold); however, induction of trans-4 (threefold), cis-3 (threefold), and trans-3 (twofold) hydroxylation did occur. Quantitatively the cis-4-hydroxy metabolite was 67of the total product by phenobarbital-induced microsomes and 21% for normal microsomes. Microsomes from animals pretreated wit- 3-methyl-cholanthrene gave about the same rate and product distribution that normal microsomes gave. A mixture of 80% carbon monoxide-20% oxygen inhibited formation of all four hydroxy metabolites with the inhibition ranging from 55 to 78%.

Animals↗
PubMed1981

Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.

Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.

Alkylation↗
PubMed1981

Metabolism of 1,3-bis(2-chloroethyl)-1-nitrosourea by rat hepatic microsomes.

The in vitro metabolism of the anticancer agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been studied in male Fischer 344 rat liver microsomal preparations. The previously identified product. 1,3-bis(2-chloroethyl)urea (BCU), has been shown to be the major metabolite. Stable isotope labeling and mass spectral analysis of isolated metabolites indicate that BCU is formed exclusively from the metabolic denitrosation of BCNU. The rate of BCNU chemical decomposition in rat liver microsomal preparations deficient in NADPH and the metabolic disappearance rate in preparations containing added NADPH were measured and compared with the measured rate of metabolic formation of BCU under the same conditions. The rate of NADPH-dependent BCNU metabolism and BCU formation are equal within experimental error. BCNU was found to inhibit the rat liver 9000 g supernatant metabolism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).

Animals↗
PubMed1980

Fluorinated analogues of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea: an attempt to control metabolism.

In seeking to block and thereby determine the role of the rapid in vivo hydroxylation of the cyclohexyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in relation to antitumor activity and tissue distribution, the 3-(1H-decafluorocyclohexyl) analogue (FCCNU) was synthesized. FCCNU showed marked toxicity and little activity against the intracerebral L1210 leukemia in mice. At pH 7 in phosphate buffer at room temperature FCCNU rapidly decomposed to give 1-(1H-decafluorocyclohexyl)-3-nitrosoimidazolidin-2-one (3) and thence, by loss of HF, the 1-(nonafluorocyclohexenyl) derivative (4); CCNU did not follow this decomposition pathway to any significant extent. Both 3 and 4 were unstable in the buffer, but each was isolated crystalline and characterized. The formation of 3 and 4 account for the biological properties of FCCNU.

Animals↗
PubMed1979

Reactions of 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in aqueous solution.

Products formed from the reaction of two chloroethylnitrosoureas in neutral aqueous solution have been identified and quantified. Mixture components recovered after a 1-h incubation period accounted for 75--85% of the starting nitrosourea. Approximately 65--85% of the reaction products were formed by an initial cleavage of the nitrosourea to the proposed intermediates 2-chloroethyl azohydroxide and an isocyanate and by subsequent hydrolytic reactions. A minor pathway, 5--10% of products, involves denitrosation of the nitrosourea with oxazoline formation. Stable isotope labeling and mass spectrometry have been used to determine the reaction sequence and product origins. Reaction product identification has been made using high-performance LC isolation and comparison with synthetic material.

Carmustine↗
PubMed1975

Decomposition of N-(2-chloroethyl)-N-nitrosoureas in aqueous media.

A reinvestigation of the aqueous decomposition of N-(2-chloroethyl)-N-nitrosoureas has shown that their mode of decomposition is dependent upon whether or not the solution is buffered at or near physiological pH. In distilled water, the 2-chloroethyl compounds decompose with the loss of 1 mol, or slightly less, of chloride ion per mole in nitrosourea and the formation of acetaldehyde and 3-4% of 2-chloroethanol. In buffer, the yield of 2-chloroethanol increases to 0.3-0.6 mol per mole of nitrosourea, the yield of chloride ion decreases to 0.5 mol per mole of nitrosourea, and the yield of acetaldehyde decreases to 0.1-0.4 mol per mole of nitrosourea. Evidence for the formation of the vinyl cation, a possible precursor of acetaldehyde, in these reactions is presented. In contrast to the results obtained with the N-(2-chloroethyl)-N-nitrosoureas, the decomposition of N,N'-bis(2-fluoroethy)-N-nitrosourea in distilled water gave almost 1 mol of 2-fluoroethanol per mole of nitrosourea and only 0.04 mol of acetaldehyde per mole of nitrosourea.

Carmustine↗
PubMed1975

Synthesis and biologic evaluation of major metabolites of N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea.

N-(2-chloroethyl)-N'-(cis-4-hydroxycylohexyl)-N-nitrosourea, a major metabolite of N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), and its trans isomer were prepared from the corresponding 4-aminocyclohexanols. A convenient and stereospecific precursor was found in 2-oxa-3-azabicyclo[2.2.2]oct-5-ene hydrochloride, hydrogenation giving pure cis-4-aminocyclohexanol hydrochloride. The metabolites were, at nontoxic levels, at least as active as CCNU in tests against murine leukemia L1210 implanted both intraperitoneally and intracerebrally and, on a weight basis, were more active and more toxic. These observations and previously reported metabolic studies suggest that the anticancer activity of CCNU is due primarily to its metabolites.

Animals↗
PubMed1975

Preparation of nitroso-13N-labeled nitrosoureas.

A method is described for the preparation of 13N-labeled N-nitrosoureas, specifically 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The 13N is generated as ammonia by the 12C(d,n)13N reaction on methane gas. The product is selectively trapped and subsequently oxidized to nitrous acid which reacts with the parent urea in solution to form the 13N-labeled nitrosourea.

Isotope Labeling↗
PubMed1982

Activated N-nitrosocarbamates for regioselective synthesis of N-nitrosoureas.

A practical and convenient method for synthesizing antitumor compounds, N-alkyl-N-nitrosoureas, regioselectively nitrosated on the nitrogen atom bearing the alkyl group is proposed. N-Alkyl-N-nitrosocarbamates are interesting intermediates in these syntheses and yield, by reaction with amino compounds, the regioselectively nitrosated N-alkyl-N-nitrosoureas. As an interesting example, N,N'-bis[(2-chloroethyl)nitrosocarbamoyl]cystamine, a new attractive oncostatic derivative, has been prepared. The cytotoxic activity of these various compounds were tested on L1210 leukemia.

Animals↗
PubMed1982

A new class of nitrosoureas. 4. Synthesis and antitumor activity of disaccharide derivatives of 3,3-disubstituted 1-(2-chloroethyl)-1-nitrosoureas.

A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.

Animals↗
PubMed1983

An analysis of 1-(2-chloroethyl)-1-nitrosourea activity at the cellular level.

The effect of five different 1-(2-chloroethyl)-1-nitrosoureas on the growth of cultured P388 cells has been analyzed in terms of physical, chemical, and kinetic parameters that are related to the mechanism of action of this class of cancer chemotherapeutic agent. This study correlates structure with activity at the cellular level by using a dose function that is related to the amount of active species, the (2-chloroethyl)diazonium ion, that is formed during the period of exposure of cells to drug rather than to the initial drug dose. 1-(2-Chloroethyl)-1-nitrosourea analogues that rapidly enter the P388 cells are shown to have the same activity relative to the amount of active species formed. When analyzed in this way, activity is not influenced by the structure of the N-3 substituent, lipophilicity, or carbamoylating activity. The agents 1-(2-chloroethyl)-1-nitrosourea (CNU), 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) all produce a 50% cell growth inhibition at 6 to 7 microM active species formed per cell volume. Chlorozotocin required a twofold higher effective dose to produce the same toxic effect. This decreased activity is attributed to the slow uptake of the water-soluble chlorozotocin into P388 and L1210 cells relative to the rate of chlorozotocin conversion to active species in medium. The yields to 2-chloroethanol from CNU, BCNU, and chlorozotocin were shown to be the same, indicating that these agents generate the same yield of alkylating intermediate at 37 degrees C and pH 7.4.

Animals↗
PubMed1984

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid, a nitrosourea with latent activity against an experimental solid tumor.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid (N-Me-cis-CCCNU) was synthesized in five steps from cis-4-aminocyclohexanecarboxylic acid via an N-tosylated intermediate. N-Me-cis-CCCNU, which is incapable of the facile decomposition that characterizes the clinically useful nitrosoureas, effected a significant cure rate of both early and established murine Lewis lung carcinoma, even though its in vitro half-life was approximately 5.5 times that of the unmethylated parent compound. This is the first observation of latent activity of a nitrosourea against an experimental solid tumor.

Animals↗
PubMed1988

Nitrosoureido nucleosides as potential inhibitors of nucleotide biosynthesis.

Several nitrosoureido nucleosides (3a, 3b, 5a, 7a, 7c, and 10a) designed as inhibitors of enzymes that metabolize pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The methylnitrosoureas 3a and 3b were not significantly cytotoxic to H.Ep.-2 and L1210 cells in vitro but showed moderate activity in the P388 mouse leukemia screen (79% ILS for 3a and 56% ILS for 3b). The (chloroethyl)nitrosoureas 7a and 7c inhibited proliferation of L1210 cells, were cytotoxic to H.Ep.-2 cells, and demonstrated good activity against P388 in vivo (135% ILS with one 30-day survivor for 7a and 191% ILS with two 30-day survivors for 7c). Overnight exposure of L1210 cells to 7a and 7c resulted in cell enlargement accompanied by cell lysis. Macromolecular synthesis in enlarged cells, particularly RNA and protein synthesis, was markedly increased relative to that in untreated control cells. The half-lives of each of the nitrosoureas in pH 7 buffer was determined and compared with biological activity.

Animals↗
PubMed1998

Neurotoxicity of combination chemotherapy with procarbazine, CCNU and vincristine (PCV) for recurrent glioma.

In cerebral glioma combination chemotherapy with procabazine, CCNU and vincristine (PCV) is used as adjuvant therapy in cases of recurrence. Standard PCV is usually well tolerated, but intensive PCV (CCNU 130 mg/m2 on day 1, procarbazine 75 mg/m2 on day 8-21, vincristine 1.4 mg/m2 on day 8 and 29; 6 courses every 6 weeks) is less well tolerated. We observed central neurotoxic side effects (focal neurological deficit, cognitive disturbances, slowing of EEG background activity, atrophy on cerebral MR) in combination with hematological and hepatic toxicity in four of 26 PCV treated patients with recurrent glioma. Prolonged myelo-suppression and/or ongoing (partial reversible in two patients) neurological deficit still influence daily life in three of four patients months after discontinuation of chemotherapy. Despite the fact that all four patients used anticonvulsants and have been treated with radiotherapy in the past, we have the strong impression that central neurotoxic side effects are related to intensive PCV therapy. We advocate to use the standard PCV regimen in patients with recurrent glioma, because of this potential toxicity and the lack of evidence that intensive PCV leads to better tumor control than standard PCV in cerebral glioma.

Adult↗
PubMed1998

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults.

The prognosis of patients with incompletely resected malignant brain tumors is almost fatal. In an attempt to improve the outcome of children and young adults with unfavorable brain tumors an intensive multimodal therapeutic strategy was developed combining simultaneous (hyper)fractionated external beam irradiation and conventional adjuvant chemotherapy after initial surgery. 17 patients aged between 2.10 and 25.11 years were entered into the study. 16/17 patients were treated according to the German/Austrian Pediatric Brain Tumor Study Group multicenter trial HIT '91. They are not protocol patients of this HIT '91 trial. Induction chemotherapy consisted of 2 courses of ifosfamide (3 g/m2/d) on days 1-3, etoposide (150 mg/m2/d) on days 4-6, methotrexate (5 g/m2) on days 15 and 22, cisplatin (40 mg/m2/d) and cytarabine (400 mg/m2/d) on days 29-31. Three weeks after the last dose of cisplatin/cytarabine the second course of chemotherapy was started. The last patient entered into the study received a modified therapy containing ifosfamide, cisplatin and etoposide. Synchronously at a median of 12 days after initiation of chemotherapy 12/17 patients received local radiotherapy (6000-7040 cGy) to the brain and 5/17 patients craniospinal irradiation (3520 cGy with a tumor boost of 1400-2000 cGy). 4-6 weeks after completion of the second course of chemotherapy maintenance therapy was started with carmustine (CCNU) (75 mg/m2) and carboplatin (400 mg/m2) each on day 1 and vincristine (1.5 mg/m2) on day 1, 8, 15. This course was repeated eight times every six weeks. 9/17 patients are alive at a median follow-up of 25 months (range 5-50) with 4 complete remissions, 2 partial remissions and 1 stable disease lasting 42+ months. Two patients, who initially had stable disease, progressed, but are still alive at 31+ and 41+ months after diagnosis. Median progression-free survival and median overall survival is 19 and 36 months, respectively. Hematologic and methotrexate-induced toxicity were severe and resulted in one therapy-related death. However, radiotherapy concomitant to chemotherapy appears to be an effective method of treatment for brain tumors with poor prognosis, though toxicity is severe in some cases.

Adolescent↗
PubMed1998

Bihemispheric malignant glioma: one size does not fit all.

Recurrence of malignant glioma following radiotherapy most commonly occurs in close proximity to the original contrast enhancing CT/MRI tumor volume. For this reason current radiation planning favors focal radiotherapy fields designed to cover the preoperative tumor contrast enhancing volume +/- surrounding edema with a 2-4 centimetre margin. Two patients with bifrontal malignant gliomas treated with such radiotherapy fields experienced out of field tumor progression while on treatment. Posterior extension along the corpus callosum, not evident on pretreatment imaging, was hypothesized as the cause of the geographic miss. The literature documenting recurrence patterns of malignant glioma following radiotherapy support focal field radiotherapy fields for most patients with malignant glioma. Reporting bias may exist in the literature, however, due to the whole brain radiotherapy used in older series reporting recurrence patterns and exclusion of patients with bihemispheric or more locally extensive tumors in more modern series. Tumor location and pattern of growth at presentation may be important factors in predicting patterns of spread and relapse after radiotherapy.

Adult↗
PubMed1999

Combined treatment modality for anaplastic oligodendroglioma: a phase II study.

PURPOSE: To investigate feasibility, toxicity and antitumor activity of combined surgery, postoperative radiation therapy (RT) and adjuvant chemotherapy (CHT) in adult patients with pure anaplastic oligodendroglioma (PAO) or mixed anaplastic oligoastrocytoma (MAO). METHODS: Between January 1988, and June 1993, 23 patients entered into a phase II study. After surgery, postoperative RT was administered with 60 Gy in 30 daily fractions in 30 treatment days in 6 weeks. Two weeks after RT, adjuvant 'modified' PCV (mPCV) (Procarbazine, 60 mg/m2, days 1-14; CCNU, 100 mg/m2, day 1; and vincristine, 1.4 mg/m2 (max. 2 mg), days 1 and 8) was administered every six weeks up to six cycles or until progression occurred. RESULTS: Median survival time is not attained yet, while 1-5 year survival rates are 100%, 100%, 78%, 61%, and 52%, respectively. Median time to tumor progression is not attained yet, while 1-5 year progression-free survival rates are 100%, 100%, 70%, 52%, and 52%, respectively. On univariate analysis of potential prognostic factors, sex, tumor location (frontal versus other), and histology (pure versus mixed anaplastic oligodendroglioma) were not found to influence survival. Age of < 50 years carried improved prognosis as well as Karnofsky performance status (KPS) 90-100 when compared to KPS of 70-80. Patients having tumors < or = 4 cm did better than those with tumors > 4 cm as well as those with total tumor resection when compared to those with subtotal tumor resection or biopsy only. Acute high-grade (> or = 3) CHT-related toxicity was mainly hematological with only 3 (13%) patients experiencing acute grade 4 toxicity. CONCLUSIONS: Combined treatment modality consisting of surgery, postoperative high-dose RT and mPCV chemotherapy for patients with anaplastic oligodendroglioma was effective with acceptable toxicity. Further studies are needed with more patients and longer follow-up to verify these results in this rare disease.

Adult↗