Biomedical subjects

Y F Shealy

Publications and source records attributed to Y F Shealy.

At least 37 records · Page 2Linked to original sources

PubMed1989

Affinity purification of cellular retinoic acid-binding protein on 14-carboxy-13-cis-retinamide-sepharose 4B.

A biologically active bifunctional retinoid, ethyl 14-carboxyretinoate, has been synthesized and shown to bind cellular retinoic acid (RA)-binding protein (CRABP) via its free carboxy group. We describe herein the synthesis of 14-carboxy-13-cis-retinamide-Sepharose 4B, which is an affinity matrix bearing an all-trans-RA moiety, and thus was used to purify and characterize CRABP from chick-embryo skin. An amide bond was first formed between the free carboxy group of the retinoid and a primary amino group of aminohexyl-Sepharose 4B, by reaction with carbodi-imide, and the ester group of the resin-bound retinoid was then hydrolysed in an alkaline medium. Polyacrylamide-gel electrophoresis and f.p.l.c. Superose column-chromatographic analysis demonstrated that the affinity-purified CRABP (Mr 15,000) was close to electrophoretic homogeneity (greater than 90%) and specifically interacts with RA. By using affinity gel chromatography, conversion of holo-CRABP into apo-CRABP by treatment with p-hydroxymercuribenzoate and a possible involvement of a thiol group in RA binding to CRABP were established. This affinity procedure provides several advantages: (i) 14-carboxy-13-cis-retinamide-Sepharose exhibited high efficiency and selectivity for RA-binding protein (i.e. retinol- or fatty-acid-binding proteins did not bind); (ii) the presence of the amide linkage between the ligand and the matrix makes this affinity resin relatively stable to cytosolic enzymes; and (iii) other RA-binding proteins, e.g. nuclear receptor(s), may be purified.

Animals↗

PubMed1989

Antitumor activity of 2-chloroethyl (methylsulfonyl)methanesulfonate (clomesone, NSC 33847) against selected tumor systems in mice.

Clomesone was evaluated for antitumor activity against a spectrum of animal tumor models. Clomesone exhibited significant antitumor activity against the murine L1210 leukemia implanted i.p., s.c., and intracerebrally (i.c.). Activity against s.c.-implanted tumor was largely independent of schedule and route of administration. Therapeutically optimal single-dose treatment (for tumored mice) was less toxic to nontumored mice than therapeutically optimal prolonged treatment. Clomesone also exhibited activity against other murine tumors (P388 leukemia, B16 melanoma, Lewis lung carcinoma, and M5076 sarcoma). It was active against P388 leukemia sublines resistant to cyclophosphamide, L-phenylalanine mustard, and cis-diamminedichloroplatinum(II). No activity was observed against a P388 subline resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea or against Ridgway osteogenic sarcoma, a nitrosourea-resistant murine solid tumor. Clomesone is generally as effective as the chloroethylnitrosoureas against experimental tumor models. Since clomesone does not have the hydroxyethylating and carbamoylating activities of the chloroethylnitrosoureas (which do not appear to contribute to antitumor activity), it would likely be a more toxicologically selective compound. It may prove to be less carcinogenic than the chloroethylnitrosoureas, and it may contribute less target organ toxicity and less interference with the actions of other drugs when used in combinations.

Animals↗

PubMed1989

Inhibition of Moloney murine lymphoma and sarcoma growth in vivo by dietary retinoids.

The effects of dietary retinoids on the growth of Moloney lymphoma (LSTRA) and sarcoma (MSC) in BALB/c mice were evaluated. Transplantable syngeneic Moloney lymphoma and sarcoma tumors are immunogenic. Preimmunization with LSTRA cells provides protection against subsequent challenge and sarcomas spontaneously regress following injection of an appropriate inoculum of MSC cells. In normal mice fed varying concentrations of all-trans-retinoic acid (RA) and given injections of 10(3) LSTRA cells, RA caused a dose-dependent increase in the number of survivors; 50% of the mice fed RA at 50 mg/kg of diet were long-term survivors. All animals died that were fed a control diet and challenged with 10(3) LSTRA cells. Athymic (nu/nu) mice fed RA were not protected against lymphoma growth, whereas euthymic (nu/+) mice were; therefore, the antitumor effect of RA was thymus dependent. Primary immunization with irradiated LSTRA in the presence of RA caused a significant increase in cell-mediated cytotoxicity by spleen cells at 4 days after immunization. However, challenge of animals preimmunized with LSTRA in the presence of dietary RA revealed a dose-dependent inhibition of memory. A significant reduction in MSC growth was also observed in normal mice fed 13-cis-retinoic acid (cRA). A comparison of the primary antilymphoma effect of dietary RA, cRA, N-(all-trans-retinoyl)-DL-leucine (RL), and N-(4-hydroxyphenyl)retinamide (4-HPR) revealed an efficacy hierarchy of RL greater than RA greater than cRA greater than 4-HPR with RL producing 70% long-term survivors at 115 days after challenge with 10(3) LSTRA cells. These studies indicate that retinoids can inhibit the growth of transplantable, retroviral-induced, immunogenic tumors by thymus-dependent mechanisms and that a newly synthesized retinoylamino acid (RL) is more potent than RA at inhibiting Moloney lymphoma growth.

Animals↗

PubMed1989

Synthesis and evaluation of some new retinoids for cancer chemoprevention.

Many derivatives and analogs of the natural vitamin A compounds have been synthesized, and some of these retinoids are very active in various bioassays that may be predictive for cancer chemopreventive activity. Analogs have been synthesized in which parts of one, or more, of the three traditional subdivisions of the retinoid structure--the terminal polar group, the conjugated side chain, and the cyclohexenyl region--have been altered or replaced. In addition, structural alterations have produced compounds (arotinoids) in which two, or more, aromatic rings replace much of the classical retinoid structure. Further structural modifications that effected replacement of the entire retinoid structure by aromatic groups and certain linking groups have been made. Some of the arotinoids and further structural variants, which appear superficially to represent immense alteration of the classical retinoid structure, have potent activity in various retinoid bioassays. Four types of new classical retinoids (retinoylamino acids, bifunctional analogs, retinyl ethers, and 4-oxoretinoid derivatives) have been synthesized and evaluated in our laboratories. All-trans- and 13-cis-retinoyl alpha-amino acids are active in a hamster trachea organ culture assay and show much promise in potentiating immune responses. Retinoic acid analogs that have a bifunctional terminus bind to CRABP even though they have a bulky alpha-substituent, induce differentiation of F9 embryonal carcinoma cells, and have good activity in an immune-potentiation assay. A new retinyl either, retinyl propynyl ether, has chemopreventive activity against mammary carcinogenesis in vivo. Oral administration of this retinoid produces high and sustained concentrations in the rat mammary gland. New congeners of 4-oxoretinoic acid demonstrate high activity in a spectrum of bioassays.

Animals↗

PubMed1989

Antifilarial activities of synthetic and natural retinoids in vitro.

Fourteen synthetic retinoids with known and different binding affinities to retinol binding proteins of Dirofilaria immitis, retinol, and retinoic acid were tested in vitro against female Litomosoides carinii (drug levels 20, 10, 1 nM/ml) and against microfilariae of L. carinii, Brugia malayi, B. pahangi and Acanthocheilonema viteae (drug levels 100, 20, 10, 1 nM/ml). All compounds including retinol and retinoic acid had at least some effects on the filarial parasites. Except for 3 synthetic retinoids, continuous exposure of adult L. carinii to the drugs reduced the motility of the worms completely or remarkably by day 7 of incubation in a dose and time dependent fashion. Also, the release of microfilariae was completely or remarkably suppressed in a dose and time dependent manner by 20 and 10 nM/ml of all except 4 of the retinoids. Short term exposure to the drugs (up to 20 nM/ml) for 4 h followed by subsequent incubation in drug-free medium was ineffective except for one synthetic retinoid (13-cis-N-(2-hydroxyethyl)retinamide:13-cis-Her). Effects on microfilariae were also dose and time dependent. All compounds affected markedly the motility of L. carinii microfilariae within 20 h at dose levels of 1 nM/ml and above. Microfilariae of B. malayi, B. pahangi and especially of A. viteae were generally less sensitive. Eight of the synthetic retinoids, but not retinol and retinoic acid, were effective (10 nM/ml). There were generally no correlations between the various effects of individual compounds; i.e., activities varied within one species depending on the parameters used and depending on the parasite species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Toxicologic and immunologic evaluations of N-(all-trans-retinoyl)-DL-leucine and N-(all-trans-retinoyl)glycine.

Sprague-Dawley rats were dosed by gavage daily for 28 days with 5, 15, or 50 mg/kg of N-(all-trans-retinoyl)-DL-leucine (RL), N-(all-trans-retinoyl)glycine (RG), or all-trans-retinoic acid (RA). On the basis of mortality incidence, fracture incidence, body weight, and histopathologic effects, RG was slightly to moderately less toxic than RA, and RL was significantly less toxic than RA or RG. Doses that had no effect on weight loss and produced no bone fractures were approximately 5 and 15 mg/kg/day for RA administered to males or females, respectively; greater than 15 mg/kg/day for RG administered to males or females; and greater than 50 mg/kg/day for RL administered to males or females. At these doses, RA and RG produced effects, detectable at the microscopic level, of lymphoid hyperplasia and hematopoietic cell proliferation in the spleen, lymphoid hyperplasia in lymph nodes, necrosis of the cortex of the thymus, hypertrophy of the zona fasciculata of the adrenal, a periportal pattern of cytoplasmic vacuolization in hepatocytes, hematopoietic cell proliferation in the liver, epithelial hyperplasia and subacute inflammation in the forestomach, and osteodystrophy. Serological alterations consisted of reduced serum albumin levels and elevated levels of triglycerides and alkaline phosphatase. For RL, similar microscopic effects, dependent on dose level and sex, were observed in spleen, thymus, adrenal, and liver. In vitro, RL was as active as RA in potentiating pokeweed mitogen-induced lymphocyte proliferation; RG was inactive. This study indicates that, relative to RA and RG, RL has less toxicity but similar immunological effects. Since RL and RG expressed little or no binding affinity for cellular RA-binding protein, the immunological effects of these retinoids may be expressed by mechanisms not linked to this protein.

Alkaline Phosphatase↗

PubMed1988

N-(Retinoyl)amino acids. Synthesis and chemopreventive activity in vitro.

N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.

Amino Acids↗

PubMed1988

Terminal bifunctional retinoids. Synthesis and evaluations related to cancer chemopreventive activity.

Retinoids that have two functional groups at the side-chain terminus have been synthesized. The two terminal functional groups are combinations of the carboxyl, carbethoxy, and N-(ethylamino)carbonyl groups. The synthesis route is based on the sodium amide catalyzed condensation of (E,E)-beta-ionylideneacetaldehyde with diethyl isopropylidenemalonate. Ethyl 14-carboxyretinoate (6), the initial bifunctional analogue, undergoes isomerization in unbuffered aqueous ethanol and reaches a state of equilibrium with ethyl 14-carboxy-13-cis-retinoate. Both of the possible amide-esters and amide-acids were obtained. The structures of the isomeric bifunctional analogues were established by studies of nuclear Overhauser effects. The bifunctional analogues induce differentiation of mouse embryonal carcinoma cells, and those analogues that have a free carboxyl group bind to cellular retinoic acid binding protein.

Animals↗

PubMed1988

Effect of the N-glycosidic bond conformation and modifications in the pentose moiety on the binding of nucleoside ligands to uridine phosphorylase.

Several arabinosyl-, xylosyl-, lyxosyl, 5'-deoxy-, acyclo-, 2,2'-anhydro-, 2,3'-anhydro-2'-deoxy-, 2,5'-anhydro-, 6,5'-cyclo-, and carbocyclic analogues of uridine with various 5-substitutions (fluoro, methyl, bromo, ethyl, benzyl, or benzyloxybenzyl) have been tested and compared with their corresponding ribo- and 2'-deoxyribosides for their potency to inhibit uridine phosphorylase (UrdPase) from both mouse and human livers. The effect of the alpha- and beta-configurations of the glycosidic bond was also tested. Xylo-, lyxo-, 2,3'-anhydro-2'-deoxy-, 6,5'-cyclo-, and carbocyclic uridines did not bind to the enzyme. Ribosides bound better than the corresponding 2'-deoxyribosides, which were better than the 5'-deoxyribosides. 2'-alpha-Deoxyribosides bound to the enzyme, albeit less tightly than the corresponding beta-anomers. The acyclo- and 2,2'-anhydrouridines were all potent inhibitors with the 2,2'-anhydro- derivatives being the most potent. 2,5'-Anhydrouridine bound to UrdPase less effectively than 2,2'-anhydrouridine and acyclouridine. Arabinosyl uracil was at best a very poor inhibitor but binds better if a benzyl group is added at the 5-position of the pyrimidine ring. This binding was enhanced further by adding a 5-benzyloxybenzyl group. A similar enhancement of the binding with increased hydrophobicity at the 5-position of the pyrimidine ring was observed with ribosides, alpha- and beta-anomers of the 2'-deoxyribosides, acyclonucleosides, and 2,2'-anhydronucleosides. The inhibitory potencies of these compounds with UrdPase from human liver roughly parallel those obtained with UrdPase from mouse liver. It is concluded that the presence of a N-glycosidic bond as well as a properly oriented 3'-hydroxyl group are prerequisites for a nucleoside ligand to bind to UrdPase. On the other hand, the presence of a 2'- or 5'-hydroxyl group or an N-glycosidic bond in the beta-configuration enhances but is not essential for binding. Furthermore, the potency of the binding of 2,2'-anhydrouridines (fixed syn-isomers) in contrast to the complete lack of binding of the 6,5'-cyclouridines (fixed anti-isomers) to UrdPase indicates that the binding of ligands to this enzyme is in the syn-conformation around the N-glycosidic bond.

Isomerism↗

PubMed1987

Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2'-deoxyguanosine enantiomers.

The action of adenosine deaminase on racemic carbocyclic analogues of 6-aminopurine nucleosides was investigated. When either racemic carbocyclic adenosine [(+/-)-C-Ado] or the racemic carbocyclic analogue [(+/-)-C-2,6-DAP-2'-dR] of 2,6-diaminopurine 2'-deoxyribofuranoside was incubated with this enzyme, approximately half of the material was deaminated rapidly. From the resulting solution, the D isomers of the deaminated carbocyclic analogues (D-carbocyclic inosine, D-C-Ino, or D-carbocyclic 2'-deoxyguanosine, D-2'-CDG) and the L isomers of the undeaminated carbocyclic analogues were isolated. At higher concentrations of the enzyme, deamination of L-C-Ado and L-C-2,6-DAP-2'-dR proceeded slowly, thus also making the other enantiomers accessible. In tests in vitro against herpes simplex virus, types 1 and 2, D-2'-CDG was as active and potent as (+/-)-2'-CDG, whereas L-2'-CDG displayed only modest activity. In contrast to the previously reported high activity and potency of (+/-)-C-2,6-DAP-2'-dR against these two viruses, L-C-2,6-DAP-2'-dR was inactive.

2-Aminopurine↗

PubMed1987

Synthesis and antiviral evaluation of carbocyclic analogues of 2-amino-6-substituted-purine 3'-deoxyribofuranosides.

Carbocyclic analogues of 2-amino-6-substituted-purine 3'-deoxyribofuranosides were synthesized by beginning with (+/-)-(1 alpha,3 alpha,4 beta)-3-amino-4-hydroxycyclopentanemethanol and 2-amino-4,6-dichloropyrimidine. The route parallels the earlier syntheses of the corresponding ribofuranoside and 2'-deoxyribofuranoside analogues. The 2-amino-6-chloropurine, guanine, and 2,6-diaminopurine derivatives and the analogous 8-azapurines were prepared. The analogue (3'-CDG) of 3'-deoxyguanosine is active in vitro against a strain of type 1 herpes simplex virus (HSV-1) that induces thymidine kinase and is modestly active against a thymidine kinase inducing strain of type 2 HSV. 3'-CDG is not active against a strain of HSV-1 that lacks the thymidine kinase inducing capacity, whereas the carbocyclic analogue of 2-amino-6-chloropurine 3'-deoxyribofuranoside is active against that strain. The carbocyclic analogue of 2,6-diaminopurine 3'-deoxyribofuranoside displayed modest activity in vitro against influenza virus.

Animals↗

PubMed1986

Synthesis and antiviral activity of the carbocyclic analogues of 5-ethyl-2'-deoxyuridine and of 5-ethynyl-2'-deoxyuridine.

The carbocyclic analogue of the antiviral agent 5-ethyl-2'-deoxyuridine (EDU) was synthesized by two routes. The pivotal step in the first route is the reaction of lithium dimethylcuprate with the carbocyclic analogue of 5-(bromomethyl)-2'-deoxyuridine dibenzoate (6). The second route is based on the synthesis of the carbocyclic analogue of 5-ethynyl-2'-deoxyuridine (12) by a coupling reaction catalyzed by bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide, a method reported recently (Robins and Barr) for the synthesis of the true nucleoside 5-ethynyl-2'-deoxyuridine (1b). The carbocyclic analogue of EDU inhibits the replication of type 1 and type 2 herpes simplex viruses in Vero cells. The carbocyclic analogue of 5-ethynyl-2'-deoxyuridine has modest activity against herpes simplex virus, types 1 and 2.

Antiviral Agents↗

PubMed1986

Carbocyclic analogues of 5'-amino-5'-deoxy- and 3'-amino-3'-deoxythymidines.

The carbocyclic analogue of 5'-amino-5'-deoxythymidine was synthesized from the carbocyclic analogue of 2,5'-O-anhydrothymidine acetate. The carbocyclic analogues of 3'-amino-3'-deoxythymidine and of 1-(3'-amino-2',3'-di-deoxylyxofuranosyl)thymine (an all-cis structure) were synthesized from the carbocyclic analogues of 5'-O-trityl-2,3'-O-anhydrothymidine and 5'-O-trityl-3'-O-(methylsulfonyl)thymidine, respectively. The carbocyclic analogue of 5'-amino-5'-deoxythymidine inhibited cytopathogenic effects (CPE) induced by a TK+ strain of type 1 herpes simplex virus replicating in L929 (mouse connective tissue) cells, but it did not inhibit CPE in Vero cells. In contrast, the all-cis-3'-azido-3'-deoxythymidine analogue demonstrated modest inhibition of CPE in Vero cells, but not in L929 cells.

Animals↗

PubMed1986

Carbocyclic analogues of 5-halocytosine nucleosides.

Carbocyclic analogues of 5-halocytosine nucleosides were prepared by direct halogenation of the carbocyclic analogues of cytidine, 2'-deoxycytidine, 3'-deoxycytidine, or ara-C. The 5-chloro and 5-bromo derivatives of the cytidine (carbodine) and of the 2'-deoxycytidine analogues and the 5-iodo derivatives of all four of the cytosine nucleoside analogues were prepared. All of the C-5-halocytosine nucleosides, as well as the parent C-cytosine nucleosides, were tested against a strain of herpes simplex virus type 1 (HSV-1) that induces thymidine kinase in host cells. Carbodine, 5-bromocarbodine, C-2'-deoxycytidine, C-5-bromo-2'-deoxycytidine, the four C-5-iodocytosine nucleosides, and C-ara-C inhibited replication of this strain of HSV-1 in cultured cells. Most of these compounds were tested also against the type 2 virus (HSV-2) in vitro and were active. The greatest activity observed was exerted by C-5-iodo-2'-deoxycytidine in inhibiting replication of HSV-1 in L929 cells. In tests against these DNA viruses, carbodine, a ribofuranoside analogue that had been shown previously to be highly active against human influenza A virus in vitro, was the most active compound against HSV-2 and one of the most active compounds against HSV-1 in Vero cells. 5-Bromocarbodine was active against influenza virus, but it was less active than carbodine.

Bromodeoxycytidine↗

PubMed1985

Inhibition of utilization of hypoxanthine and guanine in cells treated with the carbocyclic analog of adenosine. Phosphates of carbocyclic nucleoside analogs as inhibitors of hypoxanthine (guanine) phosphoribosyltransferase.

In cell cultures treated with the carbocyclic analog of adenosine (C-Ado, (+/-)-aristeromycin), the utilization of hypoxanthine and guanine has been observed to be blocked. In an attempt to define the mechanism of this inhibition, we have reexamined the metabolism of C-Ado and its effects on the metabolism of guanine and hypoxanthine. In cultures of L1210 cells, C-Ado at a concentration of 25 microM inhibited the utilization of hypoxanthine and guanine for nucleotide synthesis by more than 90% but produced little or no inhibition of the utilization of these bases in cultures of L1210/MeMPR cells which lack adenosine kinase and cannot phosphorylate C-Ado. In cultures of mammalian cells (L1210, HEp-2, and colon-26 cells), C-Ado was converted to the triphosphate (as previously observed) and also to the triphosphate of the carbocyclic analog of guanosine. The presence of coformycin in the medium at a concentration sufficient to inhibit AMP deaminase almost completely prevented the formation of carbocyclic GTP; thus, the deamination of C-Ado monophosphate is essential for the formation of phosphates of carbocyclic guanosine. Since hypoxanthine (guanine) phosphoribosyltransferase is known to be subject to end product inhibition, it was considered likely that phosphates of carbocyclic guanosine or carbocyclic inosine, present in C-Ado-treated cells, were responsible for inhibition of utilization of hypoxanthine and guanine. The 5'-phosphates of the carbocyclic analogs of inosine and guanosine were synthesized and found to be effective inhibitors of the phosphoribosyltransferase. Carbocyclic GMP was a better inhibitor than carbocyclic IMP and was also superior to GMP and IMP; the concentration of C-GMP that produced a 50% inhibition of GMP formation was approximately 1 microM. It is probable that the presence of phosphates of carbocyclic guanosine accounts for the inhibition of utilization of hypoxanthine and guanine in C-Ado-treated cells.

Adenosine↗

PubMed1984

Chemical properties and biological effects of 2-haloethyl sulfonates.

Data for the alkylating activities, DNA cross-linking activities, and proliferation-inhibitory activities toward cultured L1210 cells for twenty-four 2-haloethyl sulfonates are reported. Previously reported activities against P388 leukemia in vivo are also presented to permit correlation of in vitro and in vivo properties. Since these compounds are believed to be 2-haloethylating agents, their properties and effects were compared with those of chlorozotocin, which is a recognized 2-chloroethylating agent. 2-Chloroethyl chloromethanesulfonate, which was the most effective compound against P388 leukemia, had a moderate level of alkylating activity and a low level of cross-linking activity, but it was quite active in inhibiting proliferation of cultured L1210 cells. Although its alkylating activity was about the same as that of chlorozotocin, it caused much less cross-linking of DNA. The in vitro tests were useful for gaining information relating structure to the individual properties, but results obtained for one of the properties might not be predictive of the relative values obtained for other properties nor for in vivo activity against P388 leukemia. These results indicate that additional experiments to define the mechanism of action of these agents are needed.

Alkanesulfonates↗

PubMed1984

Synthesis and properties of some 13-cis- and all-trans-retinamides.

Several 13-cis-retinamides were synthesized from 13-cis-retinoic acid via either 13-cis-retinoyl chloride or 13-cis-1-retinoylimidazole. All-trans-retinoylglycine was prepared from all-trans-retinoyl chloride and ethyl glycinate. Detailed procedures were developed for the preparation of other all-trans-retinamides on a large scale for studies of the chemoprevention of cancer.

Animals↗

PubMed1984

2-Chloroethyl (methylsulfonyl)methanesulfonate and related (methylsulfonyl)methanesulfonates. Antineoplastic activity in vivo.

2-Haloethyl and ethyl (methylsulfonyl)methanesulfonates were prepared via sulfene intermediates. 2-Chloroethyl (methylsulfonyl)methanesulfonate is highly active against P388 leukemia in vivo; the majority of leukemic mice treated with this compound at 50 mg/kg per day, qd 1-5, survived more than 30 days and about 37% survived for more than 60 days. 2- Fluoroethyl (methylsulfonyl)methanesulfonate is also highly effective against P388 cells in vivo, but it is more toxic. Other (methylsulfonyl)methanesulfonate esters are more active than the analogous methanesulfonates and chloromethanesulfonates .

Animals↗