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Population changes induced by acridine mustards in haploid and diploid cultured cell lines from Rana pipiens were compared to test the expectation that recessive mutations will be expressed in diploid cells with a frequency equal to the square of that in haploid cells, and to investigate the usefulness of such comparison for the screening of possible mutagens. The differences in survival frequency after treatment were much smaller than predicted on the basis of the expression of lethal (recessive) mutations alone. Survival was also affected by culture conditions, drug-resistance phenomena, and other cell properties. It is suggested that with the evolution of epigenetic processes for the production of stable phenotypes, the vertebrate cell also acquired more efficient means to prevent the expression of gene mutation and that the acridine compounds may affect both epigenetic and genetic changes.
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Twenty-seven new derivatives of the 3-N,N-bis-(2-chlorethyl)-amino-4-methyl-benzoic-acid were synthesized and pharmacologically examined. The compounds showed to be highly active in the in vitro-vivo screening models (Crocker sarcoma 180, Sa-180; Friend virus leukemia, FVL) but less active in the in vivo screening models (leukemia L-1210; L-1210; Nemeth-Kellner lympho-sarcoma, NKL). The in vivo tumor growth inhibitions show that this class of compounds has possibilities for further improvement.
This paper deals with the problem of the relative selectivity of the antitumor effect of cyclophosphamide (CP). CP and its metabolites are pharmacologically characterized by determining their chemical and biological activities in vitro and their pharmacotherapeutic properties in vivo. Of particular importance is the specificity of the cytotoxic activity (cytostatic units/mumol) in vitro and the margin of safety (therapeutic index) in vivo. The pharmacologic data reveal: a. Of the various metabolites of CP only 4-hydroxycyclophosphamide, the primary activation product, exerts a highly specific cytotoxic activity in vitro and has a wide margin of safety in vivo. b. The decisive step in toxication is the formation of the alkylating N,N-bis(2-chloroethyl)phosphorodiamidic acid after acrolein has been split off.
The mutagenicity of six heterocylic nitrogen mustards (ICR compounds) has been determined in a cultured mammalian cell system by use of resistance to the purine analog 6-thioguanine to select for mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus in Chinese hamster ovary cells. The six compounds tested are ICR 191, 170, 292, 372, 191-OH, and 170-OH. The first four contain a single 2-chloroethyl group (nitrogen half-mustard) on the side chain and are mutagenic, with the tertiary amine types (170 and 292) 3 to 5 times more mutagenic than the secondary amine types (191 and 372). The remaining two compounds (191-OH and 170-OH) are not mutagenic, indicating that the 2-chloroethyl group is needed for mutation induction.
The mutagenicity and cytotoxicity of 19 ICR compounds, including 6 reported previously, have been determined in the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyltransferase system. As with other physical and chemical agents, ICR 170 and 191 exhibit a phenotypic expression time of 7 to 9 days, independent of concentrations tested. Thirteen of these compounds are mutagenic. At equimolar concentrations, the compounds with the tertiary amine-type side chain (ICR 217, 340, 355, 368, 170, and 292) are more mutagenic than the compounds with the secondary amine-type side chain (ICR 449, 371, 191, and 372). All secondary amine types show a "plateau" in their concentration-dependent mutagenesis curves at 3 to 4 microM. Shortening of the side chain by one carbon (ICR 171) results in a reduced mutagenicity. Substitution of a sulfur atom for a nitrogen in the side chain (ICR 342) increases both mutagenicity and cytotoxicity. The presence of two 2-chloroethyl groups on the side chain (ICR 220) also results in greatly increased cytotoxicity and mutagenicity. When the 2-chloroethyl group of ICR 340, 372, 292, 191, or 170 is replaced by a 2-hydroxyethyl group (ICR 340-OH, 372-OH, 292-OH, 191-OH, or 170-OH), a mutagenically inactive compound results which remains toxic. Replacement of the amine linkage with an ether linkage (ICR 283) also yields a mutagenically inactive compound.
The nitrogen mustards 5 and 9 are synthesized as potential mammatropic antineoplastic agents from estrone via 2--4 or 6--8, respectively. 5 and 9 show a binding affinity to the cytoplasmic estrogen receptor of the rat uterus of 1--10% compared to that of estrone. Both mustard compounds are irreversibly bound to the estrogen receptor.
We have studied the effect of estradiol and the combined estradiol/nitrogen mustard compound estramustine on cell lines derived from human gastric and colorectal cancers. Significant stimulation of the two gastric and two fo the colorectal cell lines occurred at physiological concentrations of estradiol. Estramustine showed an inhibitory effect in all of the cell lines at 10 micrograms/l, and a direct dose-dependent inhibition was seen in two of the cell lines. Each of the cell lines was immunohistologically stained using the estrogen-receptor-related protein ERD5, and all of the cell lines except one were positive for this protein. The inhibitory effect of estramustine was lost with increasing concentrations of estradiol, suggesting that the effects of estramustine may be linked to estrogen receptors. We conclude that reduction of circulating levels of estradiol, or treatment with estramustine may have a beneficial effect in the palliation of gastrointestinal malignancy.
This presentation describes the action of Cytostasan, a nitrogen mustard compound of benzimidazole, on reproduction and embryonic development of Wistar rats. Single doses from 20 through 100 mg/kg body weight were given intraperitoneally on the 4th, 7th, 9th, 11th or 13th day post coitum. All test animals were sacrificed on the 20th day of pregnancy. The following parameters served as a base for evaluation: the means of implantation rates, resorption rates, fetal body weights and the number of dead and living fetuses. Malformations were detected by outer inspection for gross anomalies, by means of the razor blade technique for malformations of organs and by alizarin preparations for detecting anomalies of the osseuos skeleton. All results were compared with those of an untreated control group and evaluated by statistical means. Cytostasan exerts embryotoxic and teratogenic effects in appropriate dosage. Notwithstanding the fact of giving high doses (1/2 LD 50) there is no loss of blastocysts before implantation: the number of implantation sites equals that of the control group. The resorption rate increases at all examined days of development after application of 40 mg/kg, but 20 mg/kg exert effects only on days 4, 7, and 11 p. c. There is no action on the number of living fetuses after injection of 20 mg Cytostasan/kg body weight. After application of 40 mg/kg the number of living fetuses decreases especially on the 7th, 9th, and 13th day p. c. There is a dose-dependent stunting: the fetal body weight is not reduced after a dosage of 20 mg/kg, but 40 mg/kg cause a considerable loss of weight during embryogenesis (days 9, 11, 13). It is impossible to induce stunting during blastogenesis (days 4 and 7). The observed patterns of malformation are relatively uniform: kinked tails, omphaloceles, hydronephroses, hydrocephali. Skeletal defects are absent. The results received are compared with other findings on aklylating antitumour drugs.
All the research results summarized herein were gained in the attempt to improve selectivity in cancer chemotherapy: "Chemotherapeutic agents are not only ends in themselves, they are also beginnings,. . . Selectivity must be our goal and understanding its basis our guide to the future" (138). The development of the OAP cytostatics CP, IFO, TRO, and SUFO derives from the idea of applying the principle of transport form/active form to the highly reactive nitrogen mustard compounds. The desired conversion of the reactive nitrogen mustard into an inactive transport form (latentiation) was performed by chemical synthesis. The requirement for an enzymatic activation of the transport form to give the active form in the target organ cancer cell was met and has been shown to occur in a sequence of various metabolic reactions. The goal of a substantial increase in the therapeutic range of alkylating agents has been achieved with the development of the OAP cytostatics. The higher cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. A further increase in the cancerotoxic selectivity in OAPs was achieved by the development of mesna as a regional uroprotector. Mesna eliminates the danger of therapy-limiting urotoxic side effects of OAPs, allowing administration of higher dosages and more safely optimizing their therapeutic efficacy and partly overcoming resistance phenomena. The stabilization of the primary OAP metabolites (MAFO), opens up new possibilities in clinical therapy and in preclinical tests, for examination in the clonogenic stem cell test, for in vitro purging in ABMT, and for the regional therapy of tumors. A completely new type of therapy is emerging for OAP, specifically for low-dosage MAFO, as an immunomodulator, under certain circumstances, in combination with further substances, from the biological response modifier group.
The influence on red blood cells (RBC) of two cancerostatic-(ZIMET 3106 and ZIMET 3393) and two immunomodulating agents (ZIMET 3164 and ZIMET 86/76) administered subcutaneously, or intraperitoneally in case of the radiolabelled N-mustard compounds, to mice, was studied by means of measurements of the radiolabelled compounds in blood, by cell electrophoresis, filipin-induced hemolysis of pretreated RBC and by scanning electronmicroscopy. The portion of doses applied which binds to RBC-surface decreases in the sequence of ZIMET 3106, ZIMET 3164, ZIMET 3393 and ZIMET 86/76. However, the highest reduction of the electrophoretic mobility and protection from filipin-induced hemolysis of pretreated RBC was found with ZIMET 3164. In both tests ZIMET 86/76 proved to be ineffective. These findings are in good agreement with the modifications demonstrated in pretreated RBC after filipin-induced hemolysis by means of SEM. The results presented point to a N-mustard specific interaction between the cholesterol of the membrane and/or other membrane constituents. However, these fundamental differences found in binding affinity, surface-charges and membrane interactions caused by the chemically similar compounds cannot be attributed merely to the N-mustard group.
A procedure for the semi-quantitative determination of thiodiglycol, a metabolite of the vesicant mustard gas, in urine has been developed. Thiodiglycol was converted into mustard gas using concentrated HCl at temperatures close to 100 degrees C. The headspace of the solution containing mustard gas, was trapped on an adsorption tube filled with Tenax-GC which was subsequently analyzed by gas chromatography/mass spectrometry. Using 10 mL of urine, a detection limit of a few ng/mL of thiodiglycol was achieved. The procedure was applied to urine samples obtained from Iranian patients who were the alleged victims of an attack by chemical warfare agents (probably mustard gas). A number of control samples were investigated as well. Thiodiglycol was found in the urine of the Iranian patients in concentrations varying between 3 and 140 ng/mL. However, the detection of thiodiglycol in concentrations up to 55 ng/mL in control samples excluded the unambiguous verification of the use of mustard gas against the Iranian patients.
Improvements on a procedure for the determination of thiodiglycol in urine are presented. This procedure is based on the conversion of thiodiglycol to mustard gas with concentrated HCl followed by headspace analysis. With deuterated thiodiglycol as the internal standard, more accurate quantitative analyses are possible. Residual amounts of chlorine in the water used for preparation of standard solutions posed problems, and the reaction between chlorine and thiodiglycol in water has been studied. The possible formation of mustard gas from thiodiglycol and sodium chloride was also investigated. The modified procedure was applied to urine samples of several Iranian patients who were victims of an alleged attack with mustard gas and who were treated in European hospitals in 1986. With the exception of one relatively high value (330 ng/mL), the thiodiglycol concentrations were in the same range (10 to 100 ng/mL) as those found during an investigation in 1984. The urine of 20 male controls contained thiodiglycol amounts not above 20 ng/mL. The combined data obtained in 1984 and 1986 (25 Iranian patients and 25 controls) show statistically significant differences. Approximately 80% of the Iranian patients had levels above the 95% confidence limit calculated from the control group.
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6-Bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride has been synthesized, characterized, and evaluated for antitumor activity and bone marrow toxicity in mice. The 1D- and 2D-NMR studies show the compound to exist as a beta-anomer chair conformation (23%), alpha-anomer chair conformation (22%), and several equilibrating boat conformations or furanose forms (55%). A single ip LD10 dose of 15.0 mg/kg produced antitumor activity against the murine P388 leukemia superior to that achieved with an equitoxic dose of nitrogen mustard. In normal mice, this 15.0-mg/kg dose produced minimal depression of peripheral white blood cells and no significant decrease in absolute neutrophil counts. A reduction in toxicity was also demonstrated for human bone marrow CFU-GM, as compared with nitrogen mustard and L-PAM. This and other sugar-containing mustard compounds may represent a class of antineoplastic alkylating agents with reduced bone marrow toxicity.
Capillary column isobutane chemical ionization was found to be an excellent method for the mass spectral characterization of mustard, other sulfur vesicants and related compounds. Interpretation of [M + H]+ and fragmentation ion information afforded by this technique enabled the identification of many previously unreported mustard impurities. The developed methodology was applied to the analysis of an Iran/Iraq soil sample suspected to have been contaminated with mustard. Mustard and 17 other mustard related impurities were identified and characterized in this sample under electron impact and isobutane chemical ionization conditions.
The alkylation of the cell biopolymers (RNA, DNA, proteins) by reagents Tp'(Et)Tp'(Et)Tp'(Et)TpU(CHRCl) (1) Tp'(Et)Tp''(Et)Tp'(Et)TpU(CHRCl) (2) Tp''(Et)Tp'(Et)Tp''(Et)TpU(CHRCl) (3) Tp''(Et)Tp''(Et)Tp''(Et)TpU(CHRCl) (4) Tp(Et)Tp(Et)Tp(Et)TpU(CHRCl) (5) Tp(Et)Tp(Et)Tp(Et)Tp(Et)U(CHRCl) (6) TpTpTpTpU(CHRCl) (7) where (CHRCl) is the residue of 2',3'-O-[4-N-(2-chloroethyl)-N-methylamino]-benzylidene has been investigated in the case of the ascite carcinoma Krebs-2. p' and p" designate the enantiomeric configurations at the internucleotide phosphorus atoms of the triester fragment--Tp(Et)T--, and p designates the racemic mixture. Completely and partly ethylated reagents (1)-(6) have been found to bind to the cells 4-15 fold more effectively than the diester derivative. The concentration of reagents (1)-(6) in the cells is 2-7 fold higher than in the external medium. Among the diastereomers (1)-(4) reagent (4) with the p"-configuration is the most efficient in binding with the cells 2-3 fold more efficient than reagents (1)-(3). The main targents of modifications performed in the cells by means of reagents (1)-(7) have been established. These are RNA, DNA and proteins. The share of the reagents which react with nucleic acids increases from 45% [reagent (1)] to 80% [reagent (4)], and that reacting with proteins decreases from 50 to 20% correspondingly. Reagent (4) with the p" configurations at phosphotriester fragments alkylates nucleic acids most effectively among the phosphotriester diastereomers (1)-(4): 11-fold more efficient than reagent (1) with configuration p'. The extent of modification of poly(A)+-tracts of m-RNA by reagent (4) in comparison with reagent (1) is 50-fold higher.