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PubMed1996

The interaction of 4-DAMP mustard with subtypes of the muscarinic receptor.

The compound 4-DAMP mustard (N-2-chloroethyl-4-piperidinyl diphenylacetate) is a 2-chloroethylamine derivative of the selective muscarinic antagonist 4-DAMP (N,N-dimethyl-4-piperidinyl diphenylacetate). At neutral pH, 4-DAMP mustard cyclizes spontaneously into an oziridinium ion that binds covalently with muscarinic receptors. Analysis of the kinetics of receptor alkylation showed that the interaction of 4-DAMP mustard with M2 and M3 receptors was consistent with a model in which the aziridinium ion rapidly forms a reversible complex with the receptor which converts to a covalent complex at a relatively slower rate. The rate constant (k2) for alkylation of M2 and M3 receptors was approximately the same (k2 = 0.1 min-1); however, the affinity of the aziridinium ion for the M3 receptor (KD = 7.2 nM) was approximately 6.3-fold greater than that for the M2 receptor (KD = 43 nM). The results of competitive binding experiments on Chinese hamster ovary cells transfected with the M1 - M5 subtypes of the muscarinic receptor showed that the affinity of the aziridinium ion for the M1, M3, M4 and M5 subtypes was approximately the same and about 11-fold greater than that for the M2 receptor. 4-DAMP mustard is a useful tool for selectively inactivating all non-M2 muscarinic receptors, particularly when it is used in the presence of a reversible M2 selective antagonist to protect the M2 receptor from alkylation. The results of studies on isolated smooth muscle preparations that have had their M3 receptors alkylated with 4-DAMP mustard are consistent with the postulate that the M2 receptor can elicit contraction by inhibiting the relaxant effect of isoproterenol and forskolin on histamine induced contractions.

Alkylation↗
PubMed1983

The genetic effects of the cytostatic drug TS160 on Chinese hamster fibroblasts in vitro.

The cytostatic agent TS160 inhibited DNA synthesis in V79 cells while the course of RNA synthesis and protein synthesis were not changed significantly. DNA inhibition was in direct correlation with the inhibition of growth and reduction of colony-forming ability in the treated cells. The study of the mutagenic consequences of single or repeated TS160 treatments showed that TS160 had a significant mutagenic activity on Chinese hamster V79 cells. In the study of mutagenic effects of TS160, we used the method of repeated treatment of surviving cell fractions with this compound. This method is suitable for those mutagens (e.g. weak mutagens) whose mutagenic activity on mammalian cells in vitro might escape attention after application of a single dose. The possible causes of mutagenic effects of TS160 are discussed.

Alkylating Agents↗
PubMed1986

Relationships between metabolic deactivation of ICR compounds and their differential mutagenicity in bacteria and cultured mammalian cells.

Preparations of Chinese hamster ovary (CHO) cells decreased the genotoxicity of 3 ICR compounds (ICR 191, ICR 191-OH and ICR 170-OH), while they did not affect the genotoxicity of ICR 170 in the Salmonella reversion test nor in a DNA-repair test in E. coli. These data may contribute towards the explanation of the lack of activity of the two hydroxylated compounds in the CHO/HGPRT forward mutation system, as well as the different rank of mutagenicity of the two chloroethyl compounds in bacteria (ICR 191 greater than ICR 170), compared to cultured mammalian cells and in general to eukaryotic cells (ICR 170 greater than ICR 191).

Aminacrine↗
PubMed1988

Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat--benefit of combining bisphosphonates with cytostatic agents.

This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1, 1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.

Animals↗
PubMed1977

Some clinical and pharmacological applications of high-speed liquid chromatography.

Through specific examples, the versatility of HSLC in clinical and pharmacological studies has been demonstrated. These examples are not intended to restrict the vision of the reader, like that of the author, but on the contrary, it is hoped that those not yet familiar with the usefulness of HSLC will gain perspective concerning this technique in their own fields of interest. The virtually unlimited ability to separate cellular metabolites (or other organic compounds for that matter) by HSLC is a reality at this time; however, development of more selective, sensitive means of detection and positive identification of eluting components is needed, similar to that gained by coupling mass spectrometry with gas chromatography.

Adenosine↗
PubMed1986

Interference of mouse mammary tumor virus replication by PTT.119 [p-fluoro-L-phe-m-bis-(2-chloroethyl)amino-L-phe-met ethoxy HCl]--an antitumor agent.

PTT.119 [p-fluoro-L-Phe-m-bis-(2-chloroethyl)-amino-L-Phe-Met ethoxy HCl] is a new bifunctional alkylating compound that possesses both cytolytic and antiviral activities. Continuous treatment of mouse mammary tumor cells with 15 microM PTT.119 reduced production of the B-type retrovirus murine mammary tumor virus (MuMTV). MuMTV levels in PTT.119-treated cultures were reduced by 31% in the first 24 hours; an additional 24 hours of treatment resulted in a further reduction of 70%. These reductions were significantly greater than could be accounted for by the effects of PTT.119 tumor cell metabolism and viability. Under identical treatment conditions, equimolar concentrations of L-phenylalanine mustard reduced MuMTV production by only 3%. PTT.119 inhibition of MuMTV replication was also apparent when mammary tumor cells were exposed for periods as short as 0.5-4 hours; persistent decreases in virus production were detected even 7 days following tripeptide treatment. Analyses of the polypeptide composition of MuMTV by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that virions from these PTT.119-treated mammary tumor cultures contained significant reductions in the relative level of the nonglycosylated 24,000-dalton (p24) viral polypeptide associated with the nucleoprotein core. Decreases in p24 were observed in MuMTV produced in the presence of the tripeptide and 1-7 days after removal of PTT.119. Examination of the steady-state levels and rates of intracellular MuMTV protein synthesis suggested that PTT.119 interferes with late steps in MuMTV processing and maturation.

Animals↗
PubMed1984

[Value of estramustine phosphate in the treatment of estrogen-resistant prostatic adenocarcinoma].

Estramustine phosphate ( Estracyt ) was used in 32 patients with a mean age of 73 and a half years suffering from oestrogen-resistant carcinoma of the prostate. These carcinomas were advanced and were divided into 26 stage D and 6 stage C. Treatment was given orally at a dose of 600 mg per day. Results were assessed on the basis of reliable subjective and objective selected criteria. Objective responses were obtained in 28,1% of cases and subjective responses in 40.6%. All the patients in whom there was an objective response showed a subjective response. Objective action was more marked on the primary tumour than on metastases. There was a decrease in bone pain, an improvement in general condition and disappearance of dysuria in more than a third of all cases. When there was a response, it always occurred before the end of the 2nd month and was maximal at 3 months. The mean duration of a response was 29.1 months for objective responses and 27.7 months for subjective responses. Survival of patients responding to treatment was markedly longer (by 15 months on average) than in patients who failed to respond. The low level of toxicity of the compound, even after prolonged use, makes its use possible in all patients. Thus Estracyt is felt to have a role in the treatment of the severe forms represented by hormone-resistant carcinomas of the prostate.

Adenocarcinoma↗
PubMed2006

Hybrid aza-steroid alkylators in the treatment of colon cancer.

We tested two alkylating homo-aza-steroid esters, lactandrate and lactestoxate, for antineoplastic activity against colon adenocarcinoma in vitro and in vivo. Cytostatic and cytotoxic activity was evaluated in vitro with the SRB colormetric assay against nine human colon adenocarcinoma cell lines. The in vivo anti-tumour effect was determined against two rodent colon carcinomas, the Colon 26 and the relatively chemoresistant Colon 38 carcinoma, as well as against the human xenograft CX-1 colon carcinoma. Both of the tested compounds displayed a very satisfactory anti-cancer activity in vitro and in vivo. Lactestoxate produced a significantly higher overall activity than lactandrate.

Alkylating Agents↗
PubMed1990

Nitro analogues of chlorambucil as potential hypoxia-selective anti-tumour drugs.

The chlorambucil isomer 4-[3-[N,N-bis(2-chloroethyl)amino]phenyl] butanoic acid (m-chlorambucil) has been synthesized for the first time, and the two isometric nitro derivatives of both m-chlorambucil and chlorambucil itself have been prepared as potential hypoxia-selective cytotoxins. Reduction potentials (E1/2) of the two nitro compounds were determined by cyclic voltammetry, and one-electron reduction potentials (E(1] were estimated. Both the chlorambucil isomers and the derived nitro compounds crosslink DNA, as determined by their cytotoxicity ratios in DNA repair-proficient and -deficient cell lines, but neither of the nitro derivatives showed selective toxicity under hypoxic conditions, probably due to their rather low reduction potentials.

Animals↗
PubMed1977

Chemoimmunotherapy of cancer. 3. Analytical measurement of chemical half-lives of monofunctional alkylators.

The objective of this study is the measurement of the rates of hydrolysis of a series of chloroethyl sulfide derivatives, under stimulated physiological conditions. Interferences encountered with the conventional spectrophotometric method prompted the use of a rapid-response, chloride selective electrode. This probe was readily capable of monitoring the hydrolytic rate, which is identical with the rate of chloride ion formation. Since the desired subsecond half-lives were not achieved by any of the compounds, factors influencing the rates were investigated. The results suggest that the rate-controlling cyclization step may be inhibited, due to coordination of undissociated protonic functional groups on the aromatic portions of the structures with the lone-pair electrons on sulfur.

Chemical Phenomena↗
PubMed1982

Selective deactivation of ICR mutagens as related to their distinctive pulmonary carcinogenicity.

The mutagenicity patterns and the metabolic behaviour of 4 structurally related ICR compounds were investigated using the Salmonella/microsome test. ICR 191 and ICR 170 reverted 4 his- strains (TA1537 greater than TA100 greater than TA98 and TA1538), while ICR 191-OH and ICR 170-OH reverted TA1537 only, with a narrow range of mutagenic activity. Although all the products tested were shown to contain a common mutagenic impurity, analysis of chemicals fractionated by h.p.l.c. provided evidence that pure ICR 191-OH and ICR 170-OH also induce frameshift errors. The mutagenic activity of all the 4 ICR compounds, as well as of their common impurity, was decreased in the presence of S-9 mix containing rat liver S-9 fractions, a trend confirmed by h.p.l.c. of ICR/S-9 mixtures. Despite the greater mutagenic potency in the absence of metabolic systems, ICR 191 was deactivated far more efficiently and rapidly than ICR 170 by a variety of mouse (liver greater than lung) and rat (liver greater than testis greater than kidney greater than lung greater than striated muscle greater than spleen) S-9 fractions. Mouse preparations were more effective than the corresponding rat preparations. Aroclor 1254 strongly stimulated tha activity of th NADPH-requiring enzymes responsible for ICR deactivation. H.p.l.c. analyses ruled out interconversion among the 4 ICR compounds in the presence of liver S-9 fractions, while revealing the appearance of new distinct peaks for ICR 191, ICR 170 and ICR 170-OH. The selective metabolic deactivation of ICR compounds may be related to the findings of previous carcinogenicity studies (1-3) which showed the induction of lung adenomas following i.v. but not i.p. administration of ICR 170. Conversely, ICR 191 and ICR 191-OH showed no activity even when administered i.v. Since intercalation of ICR compounds into DNA is the molecular basis for both mutagenic and antitumor activities (4), their distinctive metabolic reactivity may be also responsible for the differential efficacy in pharmacological assays.

Aminacrine↗
PubMed1984

Selective delivery of cytotoxic compounds to cells by the LDL pathway.

Cancer cells need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

Amines↗
PubMed1987

An effective mutagenic method in Azotobacter vinelandii.

The acridine-like compound ICR-191 is an effective mutagenic agent in Azotobacter vinelandii. Selectable mutants, such as those resistant to chlorate, can be isolated without post-mutagenic segregation. Non selectable mutants, such as those unable to metabolize different sugars, can be easily isolated after twelve generations of post-mutagenic segregation.

Aminacrine↗
PubMed1981

The mutagenicity of dialkylaminoalkyl chlorides in a battery of short-term assays.

Dialkylaminoalkyl chlorides, valuable chemical manufacturing intermediates, were evaluated for their mutagenicity in several short-term assays: The concentration gradient bacterial mutagen assay, the Ames test, the L5178Y mouse lymphoma cell assay, and the hepatocyte primary culture-DNA repair test. The dialkylaminoethyl chlorides were active in all test systems. The relative mutagenic potencies of the ethyl chlorides were similar in the bacterial tests and the genic potencies of the ethyl chlorides were similar in the bacterial tests and the L5178Y cell assay. The dialkylaminopropyl chlorides were weakly mutagenic in two Salmonella strains but were inactive in the other test systems. The purpose of the test battery used in these studies is to generate data on a test compound which could be used to make a rational prediction of the carcinogenic potential of the compound in test animals. On this basis, the results with the dialkylaminoethyl compounds suggest that if these agents which can form the aziridinium ion were evaluated in in vivo test there is a reasonable chance some would be found to be carcinogenic. Alternatively, the data on the dialkylaminopropyl chlorides indicate that they have a rather low carcinogenic potential.

Alkylating Agents↗
PubMed1988

Gas chromatographic retention indices of sulfur vesicants and related compounds.

Temperature-programmed retention indices, relative to a n-alkane homologous series, were determined for 37 sulfur vesicant or vesicant-related compounds using DB-1, DB-5 and DB-1701 fused-silica capillary columns. Many of the compounds, including long chain dichloro, vinylchloro, vinylalcohol and macrocyclic compounds have either not been previously identified or have not been associated with sulfur vesicant analysis. Reproducibility of the retention indices, based on Van den Dool's equation, was excellent over the course of the study. In addition, changes in retention index (delta RI), which may enable the prediction of uncharacterized homologue chromatographic behaviour, were calculated for several homologous series.

Chromatography, Gas↗
PubMed1992

Molecular conformation of estramustine and two analogues.

The crystal and molecular structures of estramustine and two of its analogues have been determined by X-ray crystallographic techniques (a total of three different compounds). The compounds studied are estramustine [1,3,5(10)-estratriene-3,17 beta-diol-3-N,N-bis(2'- chloroethyl)carbamate] and its monohydrate, estromustine [17-oxo-1,3,5(10)-estratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and 17-oxo-5-androsten-3 beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. The main structural features found are as follows: (a) the geometries of the steroid moieties are closely similar to those of the parent steroids, (b) the bonds around the nitrogen atom of the nitrogen mustard grouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perpendicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nitrogen mustard grouping makes a close contact [3.13 A], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate appears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carbamate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsible for the absence of alkylating ability and the propensity of the drug to bind microtubule-associated proteins and express an antimitotic mechanism of action.

Estramustine↗
PubMed1988

Influence of glutathione on the mutagenicity of 2-chloroethylnitrosoureas. Mutagenic potential of glutathione derivatives formed from 2-chloroethylnitrosoureas and glutathione.

2-Chloroethylnitrosoureas (CNU) are antineoplastic agents whose therapeutic dose is limited by toxic and carcinogenic side effect. The clinically used drugs, bis-(2-chloroethyl)nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HECNU) and their analogue N-(2-chloroethyl)-N-nitrosocarbamoyl-glycinamide (CNC-GA) were tested for mutagenicity and toxicity in the Salmonella typhimurium tester strain TA1535 in the presence and absence of glutathione (GSH). All 3 compounds proved to be potent mutagens. The cytotoxicity of these CNUs, however, varied depending on their carbamoylating activity. These cytotoxic effects were decreased considerably by the addition of GSH. It has been shown that the isocyanate decomposition product of the 2-chloroethylnitrosoureas reacts with GSH yielding S-carbamoylated GSH derivatives. The adducts resulting from coincubation of BCNU or HECNU with GSH, 2-chloroethyl-S-carbamoyl-GSH and 2-hydroxy-S-carbamoyl-GSH, were also tested for their mutagenic activity. While the hydroxyethylated compound exhibited no effects, 2-chloroethyl-S-carbamoyl-GSH and its cysteine analogue, 2-chloroethyl-S-carbamoyl-GSH, were strong mutagens. Further experiments with 3-chloropropyl-S-carbamoyl-GSH and t-butyl-S-carbamoyl-GSH indicate that a chlorine substituent in the beta position is necessary for the induction of a potent mutagenic response.

Carmustine↗