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At least 19 recordsLinked to original sources
PubMed1976

Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds.

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.

Acrolein↗
PubMed1984

Relationships between structures and mutagenic potencies of 16 heterocyclic nitrogen mustards (ICR compounds) in Salmonella typhimurium.

16 heterocyclic nitrogen mustards (ICR compounds), which were synthesized for use as possible antitumor agents by Creech and coworkers, were tested for mutagenicity in Salmonella typhimurium strains TA1535, TA1536, TA1537, TA1538, TA98 and TA100. The compounds were incorporated into the top agar at 5 doses: 0.5, 1, 2.5, 5 and 10 micrograms/plate. All of the compounds were negative in TA1535 except ICR 449, which was positive in all 6 strains. The other 15 compounds were positive in the remaining strains with the following exceptions: ICR 371 and 355 were negative in TA100; ICR 445 was negative in TA98 and TA100; and ICR 360 was negative in TA1537, TA1538, TA98 and TA100. Good qualitative agreement was observed between the mutagenic and antitumor activities of the 16 compounds, and between the mutagenic and carcinogenic activities of the 5 compounds that have been tested for carcinogenicity by Peck and coworkers. However, no significant correlation was found between mutagenic potency in Salmonella and antitumor potency in mice for the 16 compounds. Also, for the 5 compounds that have been tested for carcinogenicity, no significant correlation was found between their mutagenic potency in Salmonella and their carcinogenic potency in mice. In Salmonella, the secondary (2 degrees) amines generally were more mutagenic than their tertiary (3 degrees) amine homologs, although the opposite result has been reported in certain eukaryotes. Relationships between structures and potencies for the different nuclei of the 16 ICR compounds are discussed, as are similarities and differences in strain sensitivities. We conclude that the Salmonella his reversion test is not a good predictor of the antitumor and carcinogenic potencies of these ICR compounds.

Adenoma↗
PubMed1978

Mutagenicity of heterocyclic nitrogen mustards (ICR compounds) in cultured mammalian cells.

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.

Cell Line↗
PubMedDate not supplied

Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug.

The F(ab')2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme prodrug therapy (ADEPT). The prodrug, 4-[(2-chloroethyl) (2-mesyloxyethyl)amino]-benzoyl-L-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer.

Animals↗
PubMed1993

The effects of a benzoic acid mustard derivative of distamycin A (FCE 24517) and related minor groove-binding distamycin analogues on the activity of major groove-binding alkylating agents.

The distamycin derivative FCE 24517 is a potent antitumour agent. Efforts have been made towards elucidating the mechanism of action of this compound which, to date, have highlighted a high level of DNA sequence specificity for covalent adduct formation. Compared to classical alkylating agents, FCE 24517 forms very few covalent adducts with double-stranded DNA, and thus appears to be a weak alkylating agent. Examination of the effects of this minor groove-binding agent on the major groove of DNA have been facilitated by use of the alkylating agents mustine, melphalan, dabis maleate, quinacrine mustard and uracil mustard. Pretreatment of plasmid DNA with FCE 24517 followed by reaction with any one of these mustards gave rise to a marked abolition of N-7 guanine adduct formation, as assayed by Maxam and Gilbert sequencing gels. The smallest effect was seen for quinacrine mustard, whereas total abolition of N-7 guanine alkylation was seen with uracil mustard. Using related structural analogues of FCE 24517 in the same experiments, it was not possible to reproduce this effect, with very few exceptions. Some effects were seen when using distamycin A itself in these experiments, although these were marginal compared to those seen for FCE 24517. We were able to extrapolate our findings to a whole cell system using murine L-1210 leukaemia cells. Alkaline elution experiments showed that treatment of cultured cells with FCE 24517 followed by either mustine or uracil mustard caused a marked inhibition of DNA interstrand crosslink formation, compared to treatment with mustine or uracil mustard alone. The present study has demonstrated the marked effect that FCE 24517 has upon the reactivity of double-stranded DNA, an effect possibly separate from that of its alkylating function. This study has highlighted the complex nature of the DNA interactive compound FCE 24517 which possess potent and broad spectrum antitumour activity.

Alkylating Agents↗
PubMed1984

Drug-induced infertility.

Primary infertility may result from the use of various drugs. This phenomenon may be the result of an effect on the hypothalamic-pituitary-gonadal axis or a direct toxic effect on the gonads. Some of the drugs considered in this article demonstrate sex-related differences in their ability to cause infertility; there also may be age-related differences. The drugs described in this review, in regard to their association with the development of infertility, include various individual antineoplastic agents (cyclophosphamide, chlorambucil, busulphan, and methotrexate) and combinations of these chemotherapeutic drugs, glucocorticosteroids, hormonal steroids (diethylstilbestrol, medroxyprogesterone acetate, estrogen, and the constituents of oral contraceptives), antibiotics (sulfasalazine and co-trimoxazole), thyroid supplements, spironolactone, cimetidine, colchicine, marihuana, opiates, and neuroleptic agents.

Adolescent↗
PubMed1990

Thrombotic thrombocytopenic purpura and related disorders.

This article provides us with background information on the disease. Clinical features, variants and classification, laboratory findings, and pathology are discussed. Knowledge of the disease's pathogenesis has increased recently and specific causes discussed are predisposing factors, triggering agents, endothelial damage, defective PGI2 bioavailability, FVIII/vWF multimeric structure abnormalities, platelet activation, and hemolytic anemia. Proposed specific therapies discussed are steroids, heparin, antiplatelet agents, prostacyclin, splenectomy, immunosuppressive agents, plasma infusion, and plasma exchange.

Adolescent↗