Uracil Mustard Research Articles

Inhibition of nitroso chemical carcinogen activation of rat hepatic guanylate cyclase by anticancer agents.

Recent studies have demonstrated that nitroso chemical carcinogens activate guanylate cyclase (EC 4.6.1.2) which catalyzes the production of guanosine 3',5'-monophosphate. This nucleotide is thought to be involved in normal and abnormal cell growth. We examined the effect of 3 major classes of anticancer chemotherapeutic agents, the antimetabolites (methotrexate and 6-mercaptopurine), antitumor antibiotics (adriamycin and actinomycin D), and alkylating agents (cytoxan, uracil mustard, isophosphamide, chlornaphazine, and 1-propranol-3,3'-iminodimethane sulfonate) on the activation of guanylate cyclase by nitroso chemical carcinogens. The anticancer chemotherapeutic agents noncompetitively blocked the activation of rat hepatic guanylate cyclase by N'-nitro-N-nitroso-N-propylguanidine (NNPG) and hydrazine. Adriamycin, methotrexate, and uracil mustard were the most effective inhibitors completely abolishing the effect of 1 mM NNPG on guanylate cyclase activity. The remainder of the anticancer chemotherapeutic agents abolished the NNPG activation of guanylate cyclase 40--70%. Since a previously described guanylate cyclase inhibitor has been shown to terminate the growth of an undifferentiated prostatic cancer in tissue culture the present data may indicate that one of the mechanisms by which anticancer chemotherapeutic agents exert their effects is by inhibition of tumor guanylate cyclase activity.

Pulmonary Toxicity Recurring after a Six Week Course of Busulfan Therapy and after Subsequent Therapy with Uracil Mustard

A growing number of drugs, including a number of alkylating agents, have been implicated as the cause of pulmonary diseases. A patient with chronic myelogenous leukemia presented with typical cytology, biopsy, and roentgenologic findings of lung toxicity after only six weeks of therapy with busulfan. There was subsequent clearing. A similar roentgenologic change also occurred after administration of uracil mustard. This has not been reported previously.

Uracil Mustard in the Treatment of Thrombocythemia

Abstract Five patients with thrombocythemia are described. All were successfully treated with uracil mustard including two who were resistant to busulphan or radioactive phosphorus. Uracil mustard reduced the platelet count quickly and a single course of the drug produced a satisfactory remission without undue marrow depression. The results are compared with those which have been obtained with busulphan and radioactive phosphorus. It is concluded that uracil mustard may prove to be the most effective, convenient and possibly the safest, means of treating thrombocythemia.

An electron microscopic study of normal mouse lung and the early diffuse changes following uracil mustard administration

The fine structure of normal mouse lung and the early changes induced in respiratory tissue by uracil mustard, administered in a manner and dosage similar to that used by Abell et al. (1) are described. Two types of pulmonary surface epithelial cell (types I and II) were identified. No cell considered to be transitional between these two types was noted. A third type of surface epithelial cell described in rats was not seen. Two apparently distinct forms of alveolar (septal) cell were recognized. These two forms probably correspond to the two types previously identified by light microscopy. An increase in the number of ribosomes and the amount of rough endoplasmic reticulum was observed in all the types of cell in respiratory tissue during the first 6 weeks of treatment, in addition to the intranuclear inclusions seen in type II cells 4 hours after the initial injection of uracil mustard. No changes were noted in the bronchiolar epithelium.

Effect of immunosuppressive agents on normal phage-neutralizing antibody in the mouse.

The actions of three immunosuppressive drugs on normal antibody synthesis in the adult mouse were determined. Inbred mice were given daily intraperitoneal injections of actinomycin D, uracil mustard, or cyclophosphamide for extended periods. The sera of treated and untreated mice were assayed for phage-neutralizing activity to monitor the effect of each drug on the amount of circulating normal antibody. Except for an initial decrease in titer of normal anti-phage MSP2 activity, actinomycin D had no significant effect on normal antibody activity. Uracil mustard caused alternating elevation and depression of normal antibody titers. Cyclophosphamide caused a prolonged depression of normal antibody. The response patterns to the three immunosuppressive agents were the same for both induced and normal antibody.

The distribution of radioactivity from uracil mustard-2- 14C in the hepatic subcellular particulates and nucleic acids of the rat

The concentration of radioactivity in the liver particulates and in the nucleic acids of the liver, kidney, spleen, and small intestine of rats was measured after intravenous uracil mustard-2- 14C. Of the injected radioactivity 2.6% was localized in the liver at 30 minutes; the level gradually declined to 0.26% at 96 hours. The cell sap: particulate ratio was 1.5 at 30 minutes and 0.4 at 96 hours. At most time periods the concentration of radioactivity in the renal nucleic acids was significantly higher than that in the nucleic acids of the liver, spleen, and small intestine. At 1 and 3 hours the concentration of radioactivity in duodenal and jejunal RNA was not significantly different from that in renal RNA and was also higher than the concentration in the liver and spleen. Based upon the concentration of radioactivity, uracil mustard appeared to have reacted with the various nucleic acids in the range of 16,400 to 65,000 nucleotide units per molecule of uracil mustard at 1 2 hour. Only 2–3% of the radioactivity present in the liver cell was localized in nucleic acids. There was, therefore, widespread association of the radioactivity with other cellular constituents.

Effects of Tryptophan Mustard on Incorporation of Amino Acids Into Proteins In Tumor-Bearing Rats<xref ref-type="fn" rid="FN1">2</xref>

The effects of 5-[bis(2-chloroethyl)amino]-DL-tryptophan, a nitrogen mustard derivative of tryptophan, on the incorporation of amino acids into proteins have been studied in rats bearing the Walker 256 carcinosarcoma. The intravenous injection of 0.8 mg per kg of the mustard regularly induced carcinostasis and occasionally produced complete regression of the tumor. These effects were accompanied by an inhibition of the incorporation of amino acids into the proteins of the tumor. The degree of inhibition was always greater in the nuclear than in the cytoplasmic proteins, which confirmed a predominantly antinuclear action observed with other alkylating agents. The inhibition of amino acid incorporation, which followed the administration of tryptophan mustard occurred only in the tumor, while nonamino acid mustards such as nitrogen mustard (HN2) and uracil mustard had suppressive effects on the uptake of amino acids into the proteins of a number of nontumor tissues. The spleen decreased in size, but the incorporation of tryptophan into proteins of the spleen was markedly increased after treatment with tryptophan mustard. Tryptophan mustard was equally effective in the inhibition of the formation of tumor proteins from tryptophan and arginine. These data suggest that this amino acid mustard does not act as an analogue inhibitor but as an alkylating agent with altered tissue specificity.

Erratum: Alterations in Cellular Metabolism Associated with Cell Death Induced by Uracil Mustard and 6-Thioguanine

Erratum: Alterations in Cellular Metabolism Associated with Cell Death Induced by Uracil Mustard and 6-Thioguanine

Effect of Testosterone Enanthate and Alkylating Agents on Multiple Myeloma

Testosterone enanthate was used in conjunction with uracil mustard or melphalan in the treatment of seven cases of multiple myeloma. With the administration of testosterone enanthate leukopenia was not as severe after a second identical course of chemotherapy. Two additional cases were treated with testosterone enanthate alone, and subjective improvement and a rise in hemoglobin concentration occurred. This study suggests that testosterone enanthate may be a useful adjunct in the treatment of multiple myeloma with alkylating agents.

Effect of Uracil Mustard and Several Antitumor Drugs on the Primary Antibody Response in Rats and Mice

Effect of Uracil Mustard and Several Antitumor Drugs on the Primary Antibody Response in Rats and Mice

URACIL MUSTARD: A POTENT INDUCER OF LUNG TUMORS IN MICE.

Uracil mustard, injected intraperitoneally, increased the incidence and average number of pulmonary tumors in A/J mice. In comparison to a typical alkylating agent, nitrogen mustard, or to urethan, uracil mustard (on a molar basis) was considerably more carcinogenic.

URACIL MUSTARY THERAPY IN METASTATIC WILMS'S TUMOR.

The therapeutic effectiveness of uracil mustard, 5 [bis (2 chloroethyl) amino] uracil, was evaluated by the Southwest Cancer Chemotherapy Study Group in children with metastatic Wilms's tumor. This clinical trial was conducted in accordance with the Group's sensitivity spectrum protocol for the systematic investigation of new agents against solid tumors of childhood. 1 Uracil mustard, an oral alkylating agent, is a substituted mechlorethamine hydrochloride (nitrogen mustard). In comparative experiments on animal tumors, uracil mustard was more effective than either chlorambucil or nitrogen mustard. 2,3 This enhanced activity is thought to be due to an increased uptake of the uracil mustard into the desoxyribonucleic acid molecule because of the carrier action of uracil. There is no evidence that it acts as a uracil antagonist. In human malignancies it has been shown to be effective against chronic leukemias, lymphomas, and, occasionally, carcinoma of the lung and ovary and other neoplastic diseases. 4-8

Qualitative and Quantitative Tests for Uracil Mustard

Qualitative and Quantitative Tests for Uracil Mustard

Colorimetric Method for Determination of Uracil Mustard and Related Alkylating Agents

A colorimetric method for uracil mustard has been developed which is equally useful for other aromatic and aliphatic nitrogen mustard antitumor drugs. This method has been used to determine these drugs in plasma pools and for the study of their kinetics of hydrolysis and reactivity with nucleophilic reagents.

Treatment of leukaemias and reticuloses with uracil mustard.

Treatment of leukaemias and reticuloses with uracil mustard.

Effects of nitrogen mustards on the incorporation of amino acids into the proteins of tumors and other tissues; the mustard derivative of serine

The effects of O-[N-di-(2-chloroethyl)carbamoyl]- dl-serine, a nitrogen mustard derivative of serine, on the incorporation of amino acids into proteins have been studied in rats bearing the Walker 256 carcinosarcoma. The intraperitoneal injection of 1,500 mg of the compound/kg regularly induced carcinostasis and occasionally produced complete regression of the tumor, while producing minimal systemic toxicity. These effects were accompanied by an inhibition of the incorporation of amino acids into the protein of the tumor. The degree of inhibition was always greater in the nuclear proteins than in the cytoplasmic proteins, suggesting a predominantly antinuclear action which is consistent with biologic information about alkylating agents. It is proposed that these findings are related to the mechanism of action of these compounds. The inhibition observed after administration of serine mustard occurred only in the tumor, while other mustards such as HN2 and uracil mustard have been shown to inhibit these processes in a variety of nontumor tissues. Serine mustard was as effective in the inhibition of the formation of proteins from methionine as from serine. These data suggest that the compound acts not as an analogue inhibitor but as an alkylating agent with altered tissue specificity.

Intravenous Use of Uracil Mustard (U-8344): Preliminary Report

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The intravenous use of uracil mustard (U-8344).A preliminary report

The intravenous use of uracil mustard (U-8344).A preliminary report

The intravenous use of uracil mustard (U-8344). A preliminary report.

The intravenous use of uracil mustard (U-8344). A preliminary report.

Sarcoma 180 inhibition by combinations of 6-thioguanine and uracil mustard.

Combinations of 6-thioguanine and uracil mustard produced greater inhibition of the growth of sarcoma 180 than that equivalent to the sum of the inhibitory effects caused by the optimum levels of the individual drugs. This potentiation was accomplished without marked weight loss by the host. Some possible biochemical mechanisms responsible for the drug synergy are discussed.