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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.
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.
Mustard gas induces inactivation and mutation in yeast. Both effects are dose-proportional, indicating single-hit events. Induction of both effects is influenced by the cell's capacity for DNA dark-repair, whereby the probability of reversion is highest in repair-proficient cells. Binding of mustard gas to cells and probably to DNA is independent of DNA-repair systems. The number of inter-strand cross-links, as determined by assaying for renaturability of alkalidenatured DNA, increases in a dose-proportional manner. At 37% survival an excision-deficient strain contains 55 inter-strand cross-links. Chromatographic analysis yields several alkylation products of DNA. Their relative frequencies resemble the values reported for E. coli and bacteriophage T7.
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Sulphur-mustard and nitrogen-mustard are known to act as carcinogens in animal experiments. A similar effect in humans was demonstrated in 245 workers previously exposed occupationally to mustard gas and followed for over 20 years. There was a statistically significant increase in malignant tumours, especially bronchial carcinoma, bladder carcinoma and leukaemia. These findings underline the need for using alkylating agents of the mustard type exclusively in the treatment of malignant neoplasms. Immunosuppression with alkylating agents in the treatment of chronic inflammatory diseases associated with a long life expectancy is no longer justified.
A study of the mortality experience of three samples of World War I veterans totaling 7,151 U.S. white males was extended from 1956 through 1965 to learn whether a single exposure to mustard gas with respiratory injury was associated with increased risk of lung cancer in later life. Rosters of men born between 1889 and 1893 [2,718 exposed to mustard gas, 1,855 hospitalized with pneumonia in 1918, and 2,578 with wounds of the extremities (controls)] were traced via the Veterans Administration's death records. The 4,136 deaths reported were 95% of that expected. The conclusions of the original study were not altered by the additional 10 years of follow-up. Observed deaths from lung cancer numbered 69, or 2.5% for the mustard-gas group as compared to 33, or 1.8%, for the pneumonia group and 50, or 1.9%, for the controls. The risk of death from lung cancer among men gassed relative to that for the controls was estimated as 1.3, with 95% confidence limits of 0.9-1.9. These figures failed to make a strong case for a carcinogenic effect, apparently because a suffcient dose of mustard gas was not received,
Described is an acute ocular injury caused by mustard gas. The clinical course was similar to what has been established by laboratory research. Some of the histopathologic events have been discussed in theory since no tissue sample from this reported case was available for examination.
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Sulfur mustard (HD) has been shown to cause a concentration-dependent decrease in viability of human lymphocytes in vitro as measured by dye exclusion; this decrease is preventable by inhibitors of poly(adenosine diphosphatase ribose) polymerase such as niacinamide. The present study investigates the morphologic correlates of the protection afforded by niacinamide through scanning and transmission electron microscopic analysis of human lymphocytes incubated in the presence or absence of 10(3) M niacinamide for 24 h at 37 degrees C and exposed in vitro to 10(-3) M HD. Lymphocytes exposed to HD alone demonstrated 30% to 40% viability and loss of microvilli, large cytoplasmic vacuoles, extensive blebbing of the perinuclear envelope, loss of cytoplasmic organelles, condensation of nuclear chromatin, and multiple perforations of the plasmalemma. In the presence of niacinamide HD-treated lymphocytes had a viability of 87% and, except for blunting of the microvilli, essentially normal ultrastructure. Although the sequence of observed ultrastructural changes was not established, results of this morphologic study suggest that, in addition to the prevention of plasmalemmal defects and dye infusion, the mechanism of niacinamide protection appears to include preservation of the morphologic and functional integrity of cellular organelles.