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PubMed1982

The role of isocyanates in the toxicity of antitumour haloalkylnitrosoureas.

The cytotoxicity of the antitumour nitrosoureas BCNU and CCNU and the isocyanates which they liberate (chloroethylisocyanate and cyclohexylisocyanate respectively) has been measured utilising an in vitro-in vivo bioassay. Lines of the TLX5 lymphoma and L1210 leukaemia were used which were either sensitive or resistant to nitrosoureas in vivo. An estimated logarithmic cell kill produced by each compound in vitro (before injecting the cells into animals) was calculated by reference to assays of the survival time of animals given from 2 X 10(5) to 2 X 10(0) cells of each line. Resistance to both BCNU and CCNU was observed in vitro in the cell lines of the TLX5 lymphoma made resistant to either BCNU or a dimethyltriazene in vivo. The latter tumour was cross-resistant in vivo to nitrosoureas. Resistance in vitro to nitrosoureas was also observed in a line of L1210 leukaemia which had had resistance to BCNU induced in vivo. The nitrosourea resistant TLX5 lymphomas were cross-resistant in vitro to both cyclohexylisocyanate and chloroethylisocyanate whereas the nitrosourea resistant L1210 line showed no cross-resistance to cyclohexylisocyanate and marginal cross-resistance to chloroethylisocyanate. The results suggest that the TLX5 lymphoma, which is naturally resistant to alkylating agents of the 2-chloroethylamine type, may be sensitive to in vivo to nitrosoureas as a consequence of the intracellular release of isocyanates. This hypothesis was supported by the finding that the resistant TLX5 lymphoma showed no cross-resistance to other electrophilic agents, for example formaldehyde, monomethyltriazene or HN2. The transport of nitrosoureas into the sensitive and resistant cell lines was similar in profile and there was no difference in the concentration of non-protein thiols.

Animals↗
PubMed1983

Alkylating agent interactions with the nuclear matrix.

The interrelationship of DNA to the nuclear matrix is integral to the organization of chromatin within the nucleus and to the DNA replication process. The influence of nitrosourea and nitrogen mustard interactions with the nuclear matrix were studied in log phase HeLa cells. Alkylation of the nuclear matrix by chlorozotocin (CLZ) or 1-(2-chloroethyl-3-cyclohexyl)-1-nitrosourea (CCNU) was 1.58 and 1.27 pmoles drug/micrograms protein, respectively, whereas carbamoylation by CCNU was 32.5 pmoles/micrograms. These constituted approximately 30% of the total (nuclear) drug modifications. The structural matricin fibrillar components of the matrix were alkylated and carbamoylated twice as much as the ribonuclear protein elements (RNP). However, when alkylations are measured per microgram of protein, the ratio of covalently bound drug to RNP:matricin was 1.2 for both CLZ and CCNU. The RNP:matricin carbamoylation ratio for CCNU was 0.9. The importance of DNA and matrix protein alkylations to the process of reassociation was studied. Under control conditions, in vitro, approximately 80% of the DNA was associated with the matrix at a protein:DNA ratio (micrograms for micrograms) of 50:1. Direct alkylation or carbamoylation of the matrix proteins did not affect these DNA-protein interactions. However, using in vitro alkylated DNA (1 alkylation/10(2) base pairs), there was a 60% reduction of the alkylated nucleic acid bound to the matrix at the same protein: DNA ratio. The reduced binding of DNA to matrix may be a function of interference with the DNA recognition sites by alkylation of specific bases. The interference of DNA-matrix association by DNA alkylation may contribute to the cytotoxic activity of these antineoplastic agents.

Alkylating Agents↗
PubMed1984

Heme metabolism in liver and spleen of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-treated rats.

The effect of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), an anticancer alkylating agent of the nitrosourea group, on liver and spleen enzymes involved in the control of heme metabolism was studied. A single oral dose of 50 or 100 mg/kg CCNU caused a time-dependent loss in weight of both spleen and liver. Seven days after CCNU treatment (100 mg/kg) the weights were at 45 and 65% of controls respectively. The activity of delta-aminolevulinic acid synthetase (ALA-S), the rate-limiting enzyme in heme biosynthesis, declined in spleen and liver to 11 and 24% of control values, respectively, 7 days after CCNU treatment. Heme oxygenase activity, the rate-limiting enzyme of heme breakdown, was moderately increased in liver and spleen following CCNU administration. In liver, heme oxygenase activity was 142% of control values at 24 hr, and in spleen the activity was 180% of controls at 1 week. Pretreatment of the animals with phenobarbital (PB) (40 mg/kg/day, i.p.) for 4 days caused a reversal in the decline of liver weight with no effect on the decline in spleen weight following CCNU treatment. Similarly, PB pretreatment reversed the decline in hepatic ALA-S activity after CCNU administration but had no effect on the decline in splenic ALA-S activity. This study indicates that CCNU causes significant decreases in the activity of enzymes of heme biosynthesis in spleen and liver. The CCNU hemotoxicity in the liver was reversed by PB pretreatment whereas the splenic hemotoxicity was unchanged.

5-Aminolevulinate Synthetase↗
PubMed1984

Stereoselective monooxygenation of carcinostatic 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea by purified cytochrome P-450 isozymes.

Three highly purified forms of liver microsomal cytochrome P-450 (P-450a, P-450b and P-450c) from Aroclor 1254-treated rats catalyzed 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) monooxygenation in the presence of purified NADPH-cytochrome P-450 reductase, NADPH, and lipid. Differences in the regioselectivity of CCNU and MeCCNU monohydroxylation reactions by the cytochrome P-450 isozymes were observed. Cytochrome P-450-dependent monooxygenation of CCNU gave only alicyclic hydroxylation products, but monooxygenation of MeCCNU gave alicyclic hydroxylation products, an alpha-hydroxylation product on the 2-chloroethyl moiety, and a trans-4-hydroxymethyl product. A high degree of stereoselectivity for hydroxylation of CCNU and MeCCNU at the cis-4 position of the cyclohexyl ring was demonstrated. All three cytochrome P-450 isozymes were stereoselective in primarily forming the metabolite cis-4-hydroxy-trans-4-Methyl-CCNU from MeCCNU. The principal metabolite of CCNU which resulted from cytochromes P-450a and P-450b catalysis was cis-4-hydroxy CCNU, whereas the principal metabolites from cytochrome P-450c catalysis were the trans-3-hydroxy and the cis-4-hydroxy isomers. Total amounts of CCNU and MeCCNU hydroxylation with cytochrome P-450b were twice that with hepatic microsomes from Aroclor 1254-treated rats. Catalysis with cytochromes P-450a and P-450c was substantially less effective than that observed with either cytochrome P-450b or hepatic microsomes from Aroclor 1254-treated rats.

Animals↗
PubMed1985

Role of fluroacetate in the toxicity of 2-fluroethylnitrosoureas.

The possible role of fluroacetate in the toxicity and antitumour activity of the fluroethylnitrosoureas, BFNU and FCNU has been studied in CBA mice bearing the TLX5 lymphoma either sensitive (TLXS) or resistant (TLXRT) to nitrosoureas. Treatment of mice bearing either TLXS or TLXRT tumours with either BFNU or FCNU caused an elevation in the citrate levels of heart, kidney and tumour, but not the liver, 24 hr after drug administration. Heart citrate levels were maximally elevated 10-fold, while the levels in kidney and tumour were increased 3- to 6-fold. Tissue levels of flurocitrate were determined by glc after conversion to the ethyl ester. This showed maximum levels of fluroacetate production in heart, with lower levels in kidney, tumour and liver. Treatment of K562 human erythroleukaemia cells in vitro with BFNU caused an inhibition in the production of 14CO2 from 14C palmitate and [U-14C] glucose. These results suggest that some of the effects of the fluroethylnitrosoureas may be related to fluroacetate production and the consequent blocking effect on aconitase. This effect is probably related more to the generalized toxicity of these agents than to their therapeutic efficacy.

Animals↗
PubMed1986

A comparative analysis of drug-induced DNA effects in a nitrogen mustard resistant cell line expressing sensitivity to nitrosoureas.

In the Walker 256 rat mammary carcinoma cell line, WR, resistance to nitrogen mustards (NM) is accompanied by collateral sensitivity to chloroethylnitrosoureas (CENUs). DNA-interstrand cross-links, DNA-protein cross-links, and sister chromatid exchange (SCE) induction were assayed in WR and the parent cell line (WS) after treatment with nitrogen mustard (HN2), phosphoramide mustard (PM), chlorozotocin (CLZ) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Treatment of cells with HN2 caused extensive levels of cross-links, approximately 50% of which were DNA-interstrand, equal in both WR and WS, whereas PM caused no detectable cross-links in either cell line. CLZ induced low levels of DNA-interstrand cross-links, similar in WR and WS, but no DNA-interstrand cross-links could be detected in either cell line after treatment with CCNU. Both CLZ and CCNU induced low levels of DNA-protein cross-links in both cell lines, though higher in WR than WS. There was no difference in the rate of removal of HN2-induced DNA-interstrand or DNA-protein cross-links or total CLZ-induced cross-links by the two cell lines, suggesting that differential repair was not relevant to the expression of resistance. Both HN2 and PM caused more SCEs in WS than in WR, whereas CLZ and CCNU induced more SCEs in WR. Thus, NM-induced SCEs were related to cell killing but not cross-linking, whilst CENU-induced SCEs were related to cell killing and DNA-protein but not DNA-interstrand cross-links. Furthermore, the collateral sensitivity of WR cells to CENUs was not due to the differential induction of DNA-interstrand cross-links or repair of total cross-links, or repair of total cross-links, although higher levels of DNA-protein cross-links occurred in WR, and these may be either a cause or a consequence of increased susceptibility of these cells to CENUs. Presumably NMs and CENUs have several distinct and separate macromolecular targets which result in differential cell killing. It is concluded that a range of lesions occurred after treatment of WR and WS cells with either NMs or CENUs and that, in these cell lines, there is no simple correlation between drug-induced cross-linking, SCE induction and cytotoxicity.

Animals↗
PubMed1987

Misonidazole and benznidazole inhibit hydroxylation of CCNU by mouse liver microsomal cytochrome P-450 in vitro.

On the basis of promising experimental studies, the nitroimidazoles misonidazole (MISO) and benznidazole (BENZO) are under clinical investigation as chemosensitizers in combination with the chloroethylnitrosourea CCNU. We have shown previously that MISO and BENZO can alter the pharmacokinetics of CCNU leading to an improved therapeutic index in mice. Here we demonstrate using optical difference spectroscopy that MISO and BENZO are able to bind to cytochrome P-450 of mouse liver microsomes in vitro. Binding was type II in nature, indicating co-ordination of the free imidazole nitrogen with the heme moiety of cytochrome P-450. This results in an inhibition of CCNU hydroxylation by the hemoprotein. The kinetics of inhibition were of a mixed competitive-non-competitive type. At a CCNU concentration of 0.05 mM the concentrations causing 50% inhibition (I50) were 5.8 and 0.37 mM for MISO and BENZO respectively. At doses producing a similar improvement in therapeutic index in mice (2.5 mmoles/kg MISO and 0.3 mmoles/kg BENZO) the plasma and tissue concentrations achieved would inhibit CCNU hydroxylation by 30%. For BENZO, but not MISO, similar inhibition would also occur at concentrations which can be achieved safely in man.

Animals↗
PubMed1988

Inhibition of intracellular esterases by antitumour chloroethylnitrosoureas. Measurement by flow cytometry and correlation with molecular carbamoylation activity.

Antitumour chloroethylnitrosoureas (Cnus) decompose in physiological conditions yielding alkylating species and organic isocyanates. While antitumour activity is mainly attributed to the alkylation of DNA, carbamoylation of intracellular proteins by isocyanates may also have pharmacological and toxicological relevance. We previously reported a novel dynamic flow cytoenzymological assay for esterase inhibition in intact murine cells by BCNU and related isocyanates, and proposed that this might form the basis of an assay for intracellular carbamoylation. We have now examined a wide range of Cnus, isocyanates, and alkylating agents for their ability to inhibit cellular esterases. BCNU, CCNU, their derived isocyanates, and the 4-OH metabolites of CCNU exhibited potent inhibitory activity (I50 values 5.5 x 10(-5)-7.3 x 10(-4) M). Chlorozotocin and GANU were relatively inactive (I50 much greater than 10(-2) M). ACNU, TCNU and the 2-OH metabolites of CCNU exhibited intermediate activity (I50 values 1.1 x 10(-3)-2.3 x 10(-2) M). Compounds not able to form isocyanates were essentially inactive. Poor membrane permeability was also implicated in the weak activity of chlorozotocin and GANU. There was overall a good correlation between esterase inhibition and chemical carbamoylating activity, but some particular differences were identified. We concluded that flow cytoenzymological assay appears to have the potential to provide useful measurement of intracellular protein carbamoylation by existing Cnus and novel derivatives, and also offers the advantage of cell subpopulation identification for in vivo evaluation of these agents.

Animals↗
PubMed1990

Base sequence specificity of three 2-chloroethylnitrosoureas.

Chemical modifications of guanine are some of the most common results of interactions of DNA with many carcinogens and anti-cancer drugs, including nitrosoureas, nitrogen mustards, triazenes, polycyclic aromatics, and aflatoxins. The base sequence specificity for alkylation of guanines by three 2-chloroethylnitrosoureas has been determined. Guanines in the midst of a run of guanines are more susceptible than guanines in other base sequences. We have shown that certain 2-chloroethylnitrosoureas (BCNU, CCNU and methyl-CCNU) follow this same pattern. However, the quantitative degree of higher specificity for guanine with guanines as nearest neighbors depended on both the guanine position alkylated and the structure of the alkyl group attached. For example, when hydroxyethylation of runs of guanine occurred at N-7, a 6- to 11-fold increase of alkylation occurred compared to that found in the random base sequences of DNA, while hydroxyethylation at O-6 increased 1.2 to 3.5-fold and chloroethylation at N-7 was 2-to 4-fold higher than in DNA. Guanines with thymines on both the 3' and 5' sides were much less susceptible, most notably in N-7-hydroxyethylation and N-7-chloroethylation. Since guanine-rich regions are found in regulatory regions of the genome, knowledge concerning the effect of base sequence upon the production of each of the potential DNA lesions is vital to gaining an understanding of the roles of these lesions in the anti-tumor activity of a drug.

Alkylation↗
PubMed1993

Effect of N-(n-butyl)-1,3-diaminopropane on polyamine metabolism, cell growth and sensitivity to chloroethylating agents.

The effects of N-(n-butyl)-1,3-diaminopropane (BDAP) on cell growth and polyamine content were examined in L1210, SV-3T3 and HT-29 cells. In all cases, BDAP was a specific and highly effective inhibitor of spermine synthesis, and spermine levels were greatly suppressed in the presence of 50 microM BDAP. At the same time, there was a parallel increase in spermidine, which equalled or exceeded the fall in spermine so that total polyamine levels were not reduced. Cell growth was not affected in short-term experiments but culture of L1210 cells for 72-144 hr in the presence of BDAP did lead to an effect on growth that was reversed by the addition of spermine. These results suggest that, in the short term, a normal growth rate is maintained by spermidine but that a function or cellular component critically dependent on spermine becomes depleted at longer times. BDAP was a weak inducer of spermidine/spermine-N1-acetyltransferase and this enzyme may be responsible for excretion or degradation of the inhibitor. The reduction of spermine produced by BDAP led to a substantial increase in the activity of S-adenosylmethionine decarboxylase (AdoMetDC) showing that the repression of this enzyme by spermine is greater than the repression by spermidine. Although higher concentrations were required, BDAP was as effective an inhibitor of spermine synthesis as the mechanism-based inhibitor, S-adenosyl-1,12-diamino-3-thio-9-azadodecane (AdoDATAD), and produced similar decreases in spermine and increases in AdoMetDC. Prior treatment of HT-29 human colon carcinoma cells with BDAP increased the killing by chloroethylating agents but to a much smaller extent than the increase brought about by the DNA repair inhibitor, O6-benzylguanine. The effect of BDAP is likely to be due to an increased interaction of chloroethylating drugs with nuclear DNA in the absence of spermine since BDAP treatment sensitized cells even in the presence of O6-benzylguanine, which prevents repair of these lesions.

Acetyltransferases↗
PubMed1976

Dental complications of cytotoxic therapy in Hodgkin's disease--a case report.

A case of trigeminal zoster in a patient with disseminated Hodgkin's disease is described. Although one case of maxillary tooth loss in a comparable patient has previously been recorded, this is the first report of mandibular tooth loss. The aetiological significance of Beomycin and I-(2-chloroethyl)-3-cyclohexyl-I-nitrosourea (C.C.N.U.) is discussed and an hypothesis for post-zoster tooth exfoliation is suggested.

Adult↗
PubMed1984

Interaction of the oncolytic drug, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with the mixed-function oxidase system in rats.

Effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on the hepatic mixed-function oxidase system in male rats were studied both in vivo and in vitro. A single dose of CCNU (40 mg/kg) caused a significant reduction in hepatic mixed-function oxidase activities within 3 days after administration. The depression was prolonged for cytochrome P-450, total haem and the metabolism of several type I substrates lasting up to 10 weeks after a single dose. By contrast, aniline hydroxylase, cytochrome b5 and NADPH-cytochrome c reductase activities returned to near control levels after week two. Microsomal enzymes in the kidneys of treated animals however, were unaltered. Serum glutamic pyruvic and glutamic oxaloacetic transaminase and bilirubin levels, indicators of hepatotoxicity, were greatly elevated 3 days after CCNU treatment. These parameters fell rapidly but were still above control levels to the end of the 10-week study. When added in vitro, CCNU reduced apparent cytochrome P-450 content and the metabolism of type I substrates in microsomes from untreated, phenobarbital (PB) and 3-methylcholanthrene (3-MC)-pretreated rats. Total haem and NADPH-cytochrome c reductase were not affected whereas aniline hydroxylase activity was activated. CCNU interacted with hepatic microsomes to produce a type I difference spectrum.

Aniline Hydroxylase↗