The Tonkin weakfish, Cynoscion similis (Sciaenidae, Perciformes), an endemic species of the Amazonas-Orinoco Plume

Despite its importance in biogeographical, ecological, and commercial terms, the fish fauna of the northern Brazilian coast is still poorly known, representing the least sampled portion of the Brazilian Exclusive Economic Zone. We collected Tonkin weakfish, Cynoscion similis specimens during extensive surveys of the northern Brazilian coast and concluded that C. similis is common in this region. While the species had not previously been reported for the northern Brazilian state of Pará, it may have been recorded in studies of industrial fisheries, being identified only as Cynoscion sp. or by the common name pescada negra. This reinforces the need for the reliable taxonomical identification of species, to guarantee the collection of accurate data on ecology and fisheries, and ultimately, support the development of effective conservation strategies. Here we provide additional morphological and molecular data to distinguish Cynoscion similis from the closely related Cynoscion jamaicensis, and other congeners. (AU)

Transforming Growth Factor-ß1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E.

The epithelial to mesenchymal transition (EMT) imparts disease-defining properties to epithelial cells in cancer and organ fibrosis. Prior studies identify EMT control points at the level of transcription and translation, and indicate that activation of translation initiation factor 4E (eIF4E) is involved in the mechanisms coordinating these two levels of control. Here we show that 4Ei-1, a specific chemical antagonist of the eIF4E-mRNA cap interaction, potently inhibits transforming growth factor beta 1 (TGF-ß1) mediated EMT in lung epithelial cells. Upon treatment with TGF-ß1, we observed a rapid recruitment of Snail1 mRNA into the actively translated polysome pool accompanied by accumulation of the EMT transcription factor Snail1 in the nucleus. 4Ei-1 blocks ribosome recruitment to the Snail1 transcript thereby preventing accumulation of the Snail1 protein in the nucleus. Our findings establish an obligatory role for upstream translational control of downstream Snail1-mediated transcriptional events in TGF-ß1 induced EMT, and provide proof of concept for efforts to pharmacologically modulate the eIF4E-cap interaction as a means to inhibit pathological EMT in the setting of cancer and organ fibrosis.

Fluorescent tumour imaging of type I IGF receptor in vivo: comparison of antibody-conjugated quantum dots and small-molecule fluorophore.

BACKGROUND: The type I insulin-like growth factor receptor (IGF1R) is a transmembrane tyrosine kinase involved in cancer proliferation, survival, and metastasis. METHODS: In this study, we used two different fluorescent technologies (small-molecule fluorophores and quantum dot (QD) nanoparticles) to detect receptor expression and its downregulation by antibodies in vivo. RESULTS: After conjugation with AVE-1642, a humanised anti-IGF1R monoclonal antibody, both QDs (705 nm) or Alexa 680 (small-molecule fluorophore) detected expression and downregulation of IGF1R in vitro. To examine their utility in vivo, either AVE-1642 conjugates were intravenously delivered to mice bearing xenograft tumours of mouse embryo fibroblasts expressing human IGF1R or MCF-7 human breast cancer cells. Quantum dot fluorescence was mainly localised to the reticuloendothelial system in several organs and engulfed by macrophages, with only very small amount of QDs detected in the xenograft tumours. Depletion of macrophages by clodronate liposomes did not alter the nonspecific uptake of QDs. In contrast, AVE-1642-conjugated Alexa 680 solely targeted to xenograft tumour and was able to detect IGF1R downregulation, with little nonspecific targeting to other tissues or organs in mice. CONCLUSION: Taken together, our data suggest that small-molecule fluorophores, not QDs, are suitable to detect the expression and downregulation of IGF1R in vivo.

Inhibition of CMP-sialic acid transport into Golgi vesicles by nucleoside monophosphates.

We examined the interactions of nucleotides with the CMP-sialic acid transporter in order to better understand which features play a role in binding and to investigate the relationship between binding and subsequent transport. With respect to the sugar, the transporter requires a complete ribose ring for tight binding, and the 2'-ara hydrogen makes an important contact. The enzyme exhibits little specificity with respect to the 2'- and 3'-hydroxyls, as it tolerated substitutions ranging from fluorine to an azido group. In the base, the C4 amine and C2 carbonyl groups make important contacts, while the N3 nitrogen does not. However, adding a methyl group to N3 dramatically reduced binding, indicating that mass at this position sterically hinders binding. Adding a group at C5 had either no effect or slightly enhanced binding. To determine if the transporter recognizes these CMP analogues as substrates, we assayed them for their ability to trans stimulate CMP-sialic acid import. These data suggest that the enzyme transports a wide variety of NMPs, and the rate of transport is inversely proportional to the K(I) of the analogue. The importance of our findings for understanding the specificities of the different nucleotide-sugar tranlocators and the design of novel glycosylation inhibitors are discussed.

Amino acid phosphoramidate nucleosides: potential ADEPT/GDEPT substrates.

A series of aromatic, serum-stable, water soluble and nontoxic amino acid phosphoramidate monoesters of 5-fluoro-2'-deoxyuridine (FUdR) and 1-beta-arabinofuranosylcytosine (Ara-C) was shown to inhibit the cellular growth of the human leukemia cell line CCRF-CEM in the presence of human prostatic acid phosphatase (hPAP).

Comparison of the antiviral activity of hydrophobic amino acid phosphoramidate monoesters of 2'3'-dideoxyadenosine (DDA) and 3'-azido-3'-deoxythymidine (AZT).

A series of hydrophobic, water soluble and non-toxic amino acid phosphoramidate monoesters of dideoxyadenosine (ddA) and 3'-azido-3'-deoxythymidine were shown to inhibit the replication of HIV-1 in human peripheral blood mononuclear cells (PBMC) from two donors. The tryptophan methyl ester phosphoramidates of AZT and ddA were equally potent (EC50S = 0.3-0.4 microM), while the phenyl methyl ester of ddA was 40- to 100- fold more potent than the AZT derivatives. The alaninyl methyl ester of AZT was found to be 70- fold more potent than the ddA derivative. The methyl amide derivatives were found to be 5-20 fold less active than the methyl esters for the ddA series, while for AZT the derivatives were found to be of similar potency or 60- to 166- fold more potent than the methylesters.

Amino acid phosphoramidate monoesters of 3'-azido-3'-deoxythymidine: relationship between antiviral potency and intracellular metabolism.

A series of phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT) bearing aliphatic amino acid methyl esters (3a, 3c, 4a, 4c, 5-7) and methyl amides (3b, 3d, 4b, 4d) was prepared and evaluated for anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs). These compounds, which showed no cytotoxicity at concentrations of 100 microM, were effective at inhibiting HIV-1 replication at concentrations of 0.08-30 microM. Since the D-phenylalanine and D-tryptophan derivatives exhibited equivalent or enhanced antiviral activity compared to their L-counterparts, there appears to be no specific stereochemical requirement for the amino acid side chain. In addition, except for the D-phenylalanine derivatives, the methyl amides had greater antiviral activity than the corresponding methyl esters. On the basis of the observed antiviral activity of AZT phosphoramidate monoesters 3a and 4a in PBMCs and CEM cells, the mechanism of action of these two compounds was investigated. AZT-MP and substantial amounts of either phosphoramidate were detected in PBMCs and CEM cells treated with either 3a or 4a. Biological mechanistic studies demonstrated that 3a and 4a affect viral replication at a stage after virus entry and preceding viral DNA integration. Quantitation of the intracellular levels of AZT-TP in PBMCs and CEM cells treated with 3a and 4a in the presence and absence of exogenous thymidine correlated the intracellular levels of AZT-TP to the antiviral activity and suggested that AZT-TP was responsible for the activity observed. In addition, the reduced toxicity of 3a and 4a toward CEM cells relative to AZT correlated with reduced levels of total phosphorylated AZT and not AZT-TP. Stable carbamate analogues of 3a and 4a were prepared and shown to inhibit the production of AZT-MP from cell-free extracts of CEM cells, further suggesting that a phosphoramidate hydrolase may be responsible for intracellular P-N bond cleavage. Taken together, these results suggest that the biological activity and intracellular metabolism of nucleoside phosphoramidate monoesters are distinct from that of phosphoramidate diesters.

Giving the crucial information: performance on a referential communication task in Swedish children with language impairment.

The study focused on the performance of a group of Swedish children with language impairment (LI) on a referential communication task as a step in the investigation of their pragmatic skills. The task entailed choosing a single card from a selection of 16 depicting a face and describing it well enough for the opponent in order for him/her to pick the correct one from his/her identical array of cards laid out behind a barrier. To give an adequate description, the player had to understand that four dimensions had to be described in order for the other person to choose the correct card. The participating children had been part of a previous study on narrative skills in children with LI. A few of them with rather poor language comprehension had shown utterances during story generation judged to be irrelevant to both the listener and the task. In the present study, language comprehension did not significantly correlate to performance on the referential communication task. The participants performed at the level of their peers without LI and there was no significant difference between the amount of relevant or irrelevant information when the children with LI interacted with an adult or with a friend. The results are discussed in relation to recent research.

Pronucleotides: toward the in vivo delivery of antiviral and anticancer nucleotides.

To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non-toxic, stable in plasma and blood, capable of being i. v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development.

Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3'-azido-3'-deoxythymidine (AZT).

We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.

Impacts of an endophyte-infected fescue seed diet on traits of mouse lines divergently selected for response to that same diet.

In previous work, mouse lines were selected for eight generations for resistance (R) or susceptibility (S) to endophyte-infected fescue toxicosis using depression in postweaning gain caused by a toxin-containing diet as the selection criterion. Characterizing biological changes associated with resistance or susceptibility in those mice might suggest genetic or therapeutic approaches to alleviate fescue toxicosis in cattle. The first objective of the current experiment was to determine whether the toxin-containing diet depressed reproduction and mature size more severely in S than in R mice. The second was to investigate line and diet effects on hepatic glutathione-S-epoxytransferase (GST) and uridine diphosphate glucuronosyl-transferase (UDPGT) activities and to relate enzyme activities to reproduction within line by diet groups. Twenty-eight pairs per line (S or R) x diet (toxin-containing [+] or toxin-absent [-]) group cohabitated for 36 wk. The + diet depressed the number of pups born and weaned and litter weight weaned (P < .01) within the first two litters produced. Diet effects were greatest early in the experiment. Percentage changes in reproduction caused by the + diet for R and S pairs, respectively, were -13 and -28 for total pups born, -10 and -25 for total pups weaned, -13 and -14 for total litters produced, and -30 and -42 for total litter weight weaned. The S line mice were heavier than R line mice on both diets, but the + diet had a larger depressing effect on mature size of S line than of R line males (line x diet interaction, P = .09) and females (interaction not significant). Averaged across diets, GST activity was higher in R than in S dams (P = .05) at 44 wk of age but was not affected by diet or line x diet. Activity of GST was correlated with number of pups born (-.50), number of litters produced (-.44), and survival percentage (.40) within the R- group; in the R+ group, GST activity was correlated only with survival percentage (.37). In the S- and S+ groups, GST activity was not correlated with any reproductive trait. Line, diet, and their interaction did not affect UDPGT activity, and UDPGT activity was not correlated with any reproductive trait in any line x diet group. Selected lines differed in response to a toxin-containing diet as measured by its effect on reproduction and mature size. The R and S mice also differed in GST activity, but GST activity was correlated with reproductive traits only in R-line mice.

Tolerance induced by bone marrow chimerism prevents transplant vascular sclerosis in a rat model of small bowel transplant chronic rejection.

BACKGROUND: The major impediment to success in solid organ transplantation is chronic rejection (CR). The characteristic lesion of CR is transplant vascular sclerosis (TVS). Although the mechanism of TVS is thought to have an immunologic basis, in humans immunosuppression does not prevent or reverse it. One possible therapy to prevent TVS is induction of donor-specific tolerance. Bone marrow chimerism has been successful in inducing tolerance in acute and chronic rejection heart and kidney transplant models. The highly immunogenic small bowel (SB) allograft provides a rigorous test of the efficacy of this tolerance regimen. We examined whether induction of tolerance by bone marrow chimerism could prevent TVS in a model of Fisher 344 (F344) to Lewis (LEW) rat SB transplantation. METHODS: Bone marrow chimeras (BMC) were created by transplantation of T-cell-depleted F344 bone marrow into irradiated LEW rats. Chimerism was assessed by flow cytometric method. F344 SB, heterotopically transplanted into the chimeras, was clinically and histologically assessed for CR. F344 SB grafts, transplanted into cyclosporine-A-treated LEW recipients, served as control grafts for CR. RESULTS: Cyclosporine-A-treated LEW rats chronically rejected F344 SB grafts. By contrast, the BMC group demonstrated tolerance and had long-term SB graft survival (>120 days) without TVS. The BMC demonstrated immunocompetence by prompt rejection of third party ACI (RT1av1) SB allografts. CONCLUSIONS: Bone marrow chimerism prevents chronic graft failure secondary to TVS in a model of chronic SB rejection. TVS fails to develop when tolerance is established, suggesting that the mechanisms involved in TVS are, in part, immunologically mediated.

Conversation versus narration in pre-school children with language impairment.

The study focuses on two elicitation methods for language sampling in children with language impairment: conversation and narration. It has been noted in other studies on different clinical groups that language elicited in different speaking contexts varies in aspects such as MLU, fluency and syntactic complexity. The purpose of this study was to compare genre effects on different aspects of language production in a group of pre-school children with language impairment. The results show that there are differences in language production during conversation compared with narration. Intelligibility and fluency were found to be higher in conversation than in narration, whereas MLU in words was higher in narration. The narrative task elicited more phrasal expansions and grammatical morphemes per utterance than the conversation. However, the children used more complex verb forms in conversation than in narration. The results are discussed in relation to recent research.

Synthesis and antiviral activity of amino acid carbamate derivatives of AZT.

Lipophilic amino acid methyl ester and methyl amide carbamates of 3'-azido-3'-deoxythymidine (AZT) were synthesized and their anti-HIV-1 activity in PBMCs was determined. The methyl amides were more potent (EC50s = 1.8-4.0 microM) than the methyl esters (EC50s = 2.0-20 microM). Carbamate hydrolysis by cell lysates and liberation of AZT was not observed for representative methyl ester or methyl amide AZT carbamates. No evidence of direct inhibition of HIV reverse transcriptase or integrase was observed.

A rat small bowel transplant model of chronic rejection: histopathologic characteristics.

BACKGROUND: The major impediment to long-term success in solid organ transplantation is the development of chronic rejection (CR). The vascular lesion of CR, transplant vascular sclerosis (TVS) is characterized by neointimal smooth muscle cell proliferation, and is driven by both immune- and nonimmune-mediated mechanisms. Although the features of chronic heart and kidney allograft rejection have been well characterized, the more immunogenic small bowel allograft has not received similar study. METHODS: F344 small bowel (SB) was transplanted heterotopically into Lewis recipients that were treated with low-dose Cyclosporine A for 15 days. Lewis recipients of F344 or Lewis SB grafts without immunosuppression, served as controls. Grafts were assessed histologically when recipients showed clinical signs of rejection or at predetermined time points. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining. RESULTS: All SB allografts (100%) developed histologic evidence of CR Cyclosporine A. TVS was seen in 36 of the 46 (78%) of these allografts. The median time to develop TVS was 45 days. Immunohistochemical staining of chronically rejected grafts showed infiltration predominantly by CD4+ cells and macrophages, uniform up-regulation of class II MHC molecule expression, moderate to intense ICAM-1 staining in grafts harvested at postoperative day 45, and uniform neointimal cell staining for smooth muscle cell alpha-actin in the TVS lesions. CONCLUSIONS: This F344 to Lewis SB transplant model is a useful model that reproduces significant features of CR. The highly immunogenic nature of the SB allografts allows this model to serve as a stringent test for protocols designed to prevent CR.

Antiviral nucleoside drug delivery via amino acid phosphoramidates.

Stable and water soluble amino acid phosphomonoester amidates of AZT were synthesized and shown to have potent anti-HIV-1 activity. Intracellular and cell extract metabolism studies revealed that these compounds are likely to be enzymatically converted to the corresponding monophosphates. In addition, we have shown that the half life and tissue distribution of a phosphoramidate of AZT is 5 and 10-fold greater, respectively, than AZT.

Characterization of hamster recombinant monomorphic and polymorphic arylamine N-acetyltransferases: bioactivation and mechanism-based inactivation studies with N-hydroxy-2-acetylaminofluorene.

The purified hamster recombinant arylamine N-acetyltransferases (NATs), rNAT1-9 and rNAT2-70D, were characterized for their capabilities to bioactivate N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to DNA binding reactants and for their relative susceptibilities to mechanism-based inactivation by N-OH-AAF. The rate of DNA adduct formation resulting from rNAT1-9 bioactivation of [14C]N-OH-AAF was more than 30 times greater than that of rNAT2-70D-catalyzed bioactivation of [14C]N-OH-AAF. This result is consistent with substrate specificity data indicating that N-OH-AAF is a much better acetyl donor for hamster NAT1 than NAT2. Previous studies indicated that N-OH-AAF is a mechanism-based inactivator of hamster and rat NAT1. In the presence of N-OH-AAF, both rNAT1-9 and rNAT2-70D underwent irreversible, time-dependent inactivation that exhibited pseudo first-order kinetics and was saturable at higher N-OH-AAF concentrations. The enzymes were partially protected from inactivation by the presence of cofactor and substrates. The limiting rate constants (ki) and dissociation constants (Ki) for inactivation by N-OH-AAF were determined. The second-order rate constants (ki/KI) were 22.1 min-1 mM-1 for rNAT1-9 and 1.0 min-l mM-1 for rNAT2-70D, indicating that rNAT1-9 is approximately 20 times more susceptible than rNAT2-70D to inactivation by N-OH-AAF. The kinetic parameters for rNAT1-9 were nearly identical to values previously reported for partially purified hamster NAT1. Partition ratios were 504 for inactivation of rNAT1-9 by N-OH-AAF and 137 for inactivation of rNAT2-70D. Thus, a turnover of almost 4 times as many N-OH-AAF molecules is required to inactivate each molecule of rNAT1-9 than is needed to inactivate rNAT2-70D. The partition ratio data are consistent with the finding that rNAT1-9 catalyzes a higher rate of DNA adduct formation by N-OH-AAF than rNAT2-70D. The combined results indicate that the recombinant enzymes are catalytically and functionally identical to hamster NATs and, therefore, will be a useful resource for studies requiring purified NATs.

Inbreeding and reproduction in mice divergently selected for response to a dietary toxin.

This study was conducted to determine whether inbreeding coefficients of selected parents or of progeny differed between lines of mice selected for increased or decreased responsiveness to a nutritional toxicosis. A second objective was to determine whether the influence of inbreeding of parents and/or progeny on reproductive traits differed between those lines. Mice were selected divergently for 8 generations for the effect on post-weaning growth of endophyte-infected fescue seed in their diet. Forty pairs (or in Generation 7, 20 pairs) were selected and mated per generation in each line. Inbreeding increased 0.5 to 0.6% per generation in both lines, a rate close to that predicted from genetic theory. Inbreeding coefficients of selected parents were not higher in the susceptible than in the resistant line. A difference would have been expected if the inbreeding coefficient had been correlated with susceptibility to toxicosis. The magnitudes of inbreeding depression for reproductive traits did not differ significantly between lines. The average inbreeding coefficient of the potential litter tended to be higher in nonfertile than fertile matings (P = 0.10), but inbreeding coefficients of sires and dams did not differ between successful and unsuccessful matings. Inbred litters tended to be born earlier than noninbred litters (P = 0.10). Inbred dams produced smaller litters than noninbred dams (main effect P < 0.05) but only when the litter also was inbred (interaction P < 0.01). Sex ratio was not influenced by inbreeding of sire, dam or litter, but there was a higher proportion of male progeny in the susceptible than in the resistant line (P = 0.01). To avoid reduced reproductive fitness, laboratory animal populations should be managed to minimize inbreeding of progeny and dam.

Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs.

The decomposition pathways in peripheral blood mononuclear cells (PBMCs) and the in vitro anti-HIV-1 activity of the structurally similar 3'-azido-3'-deoxythymidine (AZT) phosphoramidates 1-6 and 3'-fluoro-3'-deoxythymidine (FLT) phosphoramidates 7-10 are reported. The AZT phosphoramidates exhibited no cytotoxicity toward CEM cells at concentrations as high as 100 microM, whereas the FLT phosphoramidates 9 and 10 had CC50 values of 95.6 and 35.1 microM, respectively. All 10 compounds exhibited no cytotoxicity toward PBMCs at concentrations as high as 100 microM and were effective at inhibiting viral replication. In particular, the AZT phosphomonoester amidate 4 displayed comparable antiviral activity to the parent nucleoside analog AZT. Mechanistic studies on the amino acid carbomethoxy ester phosphomonoester amidates revealed that their decomposition pathway differs from that of amino acid carbomethoxy ester aryl phosphodiester amidates of nucleotide prodrugs. AZT phosphomonoester amidates are internalized by lymphocytes to the same extent as AZT by a nonsaturable process. In lymphocytes, the amino acid carbomethoxy ester phosphomonoester amidates of AZT are not significantly metabolized to either AZT or the mono-, di-, or triphosphate of AZT. The amount of active anabolite, AZT-5'-triphosphate, formed in PBMCs incubated with the AZT phosphomonoester amidates 3 and 4 was 2- and 3-fold less than that observed after treatment with AZT, respectively. In contrast, FLT phosphomonoester amidates are rapidly converted to FLT-5'-monophosphate by a process that is antagonized by the corresponding AZT derivative 4. These results suggest that the metabolism of aromatic amino acid carbomethoxy ester phosphomonoester amidate nucleotide prodrugs by PBMCs does not require prior conversion to the corresponding carboxylic acid before proceeding to P-N bond cleavage.

Potent growth inhibitory activity of zidovudine on cultured human breast cancer cells and rat mammary tumors.

Originally designed as an antitumor agent, zidovudine (AZT) has exhibited only marginal tumor growth inhibitory activity. Recently, three abstracts have described positive clinical outcomes for a small number of patients with advanced breast cancer treated with weekly infusions of either methotrexate or cisplatin and AZT. Consequently, we conducted a preclinical study of the anti-breast cancer and anti-mammary tumor activity of AZT. Here we have demonstrated that AZT, alone, has a preferential in vitro and in vivo effect on breast and mammary cancer cells. It is 1000 times as potent as an inhibitor of the in vitro growth of the human breast cancer cell line MCF-7 (IC50 = 10 +/- 5 nM) than of the growth of the T-cell leukemia cell line CEM (IC50 = 14 +/- 2 microM). A novel mechanism for this preferential effect on growth is indicated by the 3-4-fold increase in production of phosphorylated AZT (mono-, di-, and triphosphate) in MCF-7 relative to CEM. We extended these in vitro observations to in vivo studies in rats and found that AZT is a potent in vivo inhibitor of the growth of methylnitrosourea-induced rat mammary tumors without any apparent toxic effects on internal organs. These preclinical results demonstrate, for the first time, that AZT has significant anti-breast cancer activity and strongly suggest that the clinical usefulness of this drug is worthy of investigation.