Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The triarylethylene antiestrogen clomiphene was previously shown to undergo biotransformation to an active metabolite, 4-hydroxyclomiphene, and to 3-methoxy-4-hydroxyclomiphene plus the respective regioisomers of these, 4 and 5. We now report the synthesis and further chemical and biochemical studies on 3-5. Coupling of 4-[2-(diethylamino)ethoxy]benzophenone with either 4-(benzyloxy)benzaldehyde or its 3-methoxy analogue 11b in the presence of titanium, followed by chlorination and deprotection of the intermediate triarylethylenes, gave 4 and 5, respectively. Condensation of benzylmagnesium chloride with the (2-methoxyethoxy)methyl (MEM) ether of 4-[2-(diethylamino)ethoxy]-3'-methoxy-4'-hydroxybenzophenone, followed by mild acid treatment, afforded deschloro 3 due to facile MEM ether hydrolysis. Acetylation of this, followed by chlorination and deacetylation, gave 3. Compounds 4 and 5 reacted readily with nucleophiles. In particular, 2-mercaptoethanol reacted with 4 to afford deschloro vinyl thioether 13 as suggested by NMR spectral studies, a result that implicated allene-quinone 14 as the electrophilic species produced in solution from 4. Antiestrogen binding sites and estrogen receptors from MCF 7 human breast cancer cells interacted with 3 and 5 with affinities comparable to those of tamoxifen and 1, respectively; 5 was shown not to bind irreversibly with these sites. Inhibition of MCF 7 cell proliferation by 3-5 at 5 microM concentrations (76%, 57%, and 49%, respectively, relative to drug-free controls) compared favorably to that observed with 5 microM 1 (80%). These results suggest that 3-5 as well as 2 may contribute to the antiestrogenic effects of 1.
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PMID:Phenolic metabolites of clomiphene: [(E,Z)-2-[4-(1,2-diphenyl-2-chlorovinyl)phenoxy]ethyl]diethylamine. Preparation, electrophilicity, and effects in MCF 7 breast cancer cells. 290 31

Permanent magnets offer a novel solution to the problem of shoulder implant instability when the rotator cuff has been destroyed. We report a case of their use in a 66-year-old patient with a large proximal humerol breast cancer metastasis. Humerol resection was below the deltoid insertion. The polyacetal device had samarium-cobalt magnets in the humeral head. The glenoid component (the keeper in the magnetic circuit) was made of titanium nitride-coated F17 stainless steel. The system's breakaway force was ca. 40 N. At 24 months the shoulder was free of pain and stable, with an active range of movement of 30 degrees flexion, 45 degrees external rotation, and internal rotation to T8. The patient could perform household tasks and drive an automatic car. Radiography showed no implant loosening or upward humeral head dislocation. Subsequently, the patient's condition deteriorated; at 33 months she was bedridden, and radiography showed dislocation of the humeral component.
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PMID:Total shoulder replacement by magnetic arthroplasty. 952 36

We report a case of a 28-year-old woman with right-sided breast cancer. The patient had been treated for atopic dermatitis since her infancy. She underwent breast-conserving surgery (BCS) in July 1998, and three titanium clips were placed at the margin of the excision cavity at the time of surgery. Two months after surgery, the patient exhibited a rapid exacerbation of atopic dermatitis. Various drugs were suspected to be the cause of the allergic reaction, but the results of a bi-digital O-ring test (BDORT) suggested an allergic reaction to titanium clips. In August 1999, the patient underwent a second operation to remove the titanium clips under local anesthesia. Allergy to surgical titanium clips is a rare complication, but in patients with a history of severe allergic diseases, a preoperative immunologic examination should be performed and the patient's history of metal allergy should be investigated.
Breast Cancer 2001
PMID:A case of allergic reaction to surgical metal clips inserted for postoperative boost irradiation in a patient undergoing breast-conserving therapy. 1118 Jul 73

We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin 4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4beta,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.
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PMID:Studies in polyphenol chemistry and bioactivity. 4.(1) Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4beta,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest. 1260 75

The patient was a 54-year-old woman with a dermatopleural fistula and necrosis of the third to the fifth anterior ribs after postoperative adjuvant radiation for right breast cancer. After resection of the chest wall and combined partial resection of the right upper and middle lobes of the lung, the thoracic cage defect was stabilized by titanium micromesh and the soft tissue defect was covered by an ipsilateral pedicled latissimus dorsi musculocutaneous flap. The dorsal skin defect was covered by split-thickness skin grafts 3 weeks later. The advantages of titanium micromesh lie not only in its good biocompatibility and mechanical strength, but also in its light weight and low radiological interference. No paradoxical movement or other prosthesis-related complications occurred during the follow-up period. Thus, we consider that titanium micromesh is a suitable material to use in the reconstruction of a large chest wall defect.
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PMID:Large chest wall reconstruction using titanium micromesh and a pedicled latissimus dorsi musculocutaneous flap: report of a case. 1562 68

[1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride is a newly synthesized transition metal-based anti-cancer drug. We studied the anti-tumor activity of this drug (final concentrations: 25, 250 and 2,500 micromol/l) against freshly explanted human tumors, using an in vitro soft agar cloning system. A total of eight tumor samples were evaluated using 1-h exposures. Additionally, the breast carcinoma cell line MCF-7 was examined with regard to sensitivity. The tested compound was markedly active against one renal cancer sample, whereas other renal tumors were resistant. Concentration-dependent anti-tumor activity was demonstrated for all samples except for melanoma. At concentrations of 250 micromol/l or less, the compound was less active than cisplatin or equally active at 0.2 microg/ml, whereas at 2,500 micromol/l it showed a significant cytotoxic activity against a wide spectrum of tumor types. The highest activity was observed against renal carcinomas (three of three tumor specimens inhibited at 2,500 micromol/l). Sensitivity was also highly remarkable in the breast cancer cell line MCF-7 inhibited in a range of 25-2,500 micromol/l, whereas melanoma cells seemed to be profoundly resistant. Further clinical development of this drug appears warranted because of the broad cytotoxic activity shown.
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PMID:Activity of [1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride against tumor colony-forming units. 1622 48

The selective oestrogen receptor modulator tamoxifen is a leading agent in the adjuvant treatment of breast cancer. Several organometallic moieties have been vectorised with tamoxifen, in order to improve on the latter's antiproliferative properties by the addition of a potentially cytotoxic moiety, and have been evaluated versus both oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB231) breast cancer cells. For tamoxifen analogues with ((R,R)-trans-1,2-diaminocyclohexane)platinum(II), cyclopentadienyl rhenium tricarbonyl, and ruthenocene tethers, there was no enhancement of the antiproliferative effect on oestrogen receptor positive cells, nor any cytotoxic effect on oestrogen receptor negative cells, while those containing cyclopentadienyl titanium dichloride showed an oestrogenic effect. However, compounds where ferrocene replaces tamoxifen's phenyl ring were strongly cytotoxic against both cell lines. The synthesis and biological results of these compounds is reviewed and placed in the historic context of inorganic compounds in therapy.
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PMID:Metal complex SERMs (selective oestrogen receptor modulators). The influence of different metal units on breast cancer cell antiproliferative effects. 1640 38

The nonsteroidal antiestrogen drug tamoxifen is the endocrine treatment of choice for estrogen receptor positive breast cancer, while the related estrogen receptor antagonist raloxifene is an effective therapeutic intervention for osteoporosis. We report the development of a series of hydroxylated 2-benzyl-1,1-diarylbut-2-enes containing a flexible core scaffold structure differing from the 1,1,2-triarylethylene typical of tamoxifen analogues. In this novel structure, a benzylic methylene group acts as a flexible hinge linking the aryl ring C and the ethylene group. The target products were synthesized using a McMurry coupling (titanium tetrachloride/zinc mediated) procedure. In this study, introduction of hydroxyl, ether and ester substitution on ring C was explored in an attempt to correlate possible metabolic activation in Ring C with antiproliferative activity. These Ring C substituted products showed potent antiproliferative activity against the MCF-7 human breast cancer cell line. The compounds were also shown to have high binding affinity for the estrogen receptor (IC(50) values in the low nanomolar range) together with up to 17 fold selectivity for ERalpha/beta. Some compounds demonstrated antiestrogenic activity in the Ishikawa cells at 40 nM without estrogenic stimulation. The products also displayed a pro-apoptotic effect in MCF-7 cells in a flow cytometry based assay. In a computational study, docked structures of the active compounds were compared with the X-ray crystal structures for the complexes of ERalpha with 4-hydroxytamoxifen and ERbeta with raloxifene. The novel ligands are predicted to bind to the ERalpha and ERbeta in an antiestrogenic orientation, with expected differences obtained in the alignment of the benzylic ring C within the ligand binding domain.
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PMID:Antiestrogenically active 2-benzyl-1,1-diarylbut-2-enes: synthesis, structure-activity relationships and molecular modeling study for flexible estrogen receptor antagonists. 1678 64

Estrogen receptors are therapeutic intervention targets for diseases such as osteoporosis and breast cancer with both tamoxifen and raloxifene established as clinical estrogen receptor antagonists. We report a series of novel selective estrogen receptor modulators (SERMs) whose structures are based on a flexible core scaffold differing from the triphenylethylene of tamoxifen analogues through the insertion of a benzylic methylene group as a flexible spacer between the aryl ring C and the ethylene group. A facile synthesis of the target compounds utilises the titanium tetrachloride/zinc mediated McMurry coupling reaction. Successive introduction onto the parent scaffold of hydroxyl functional groups afforded a series of increased potency ligands for the ER - essentially exploring the predicted in vivo metabolic activation of such aromatic SERM ligands. This second generation compound series demonstrated high antiproliferative potency against the MCF-7 human breast cancer cell line, with low cytotoxicity. High ER binding affinity (IC50 20 nM) together with up to 12 fold ERalpha/beta selectivity was also observed. In addition, the compounds displayed antiestrogenic effects at 40 nM when evaluated in the Ishikawa cell line with little estrogenic stimulation. Representative ligands were shown to be pro-apoptotic in human MCF-7 cells in a FACS based assay. Comparison of the docked structure obtained for the most active compound with the X-ray crystal structure reported for the complex of ERalpha and 4-hydroxytamoxifen, predict that these ligands bind in an antiestrogenic manner with some differences being observed in the benzylic Ring C orientation, as expected. This work further demonstrates the tolerance of the estrogen receptor towards flexible modulators.
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PMID:Synthesis, structure-activity relationships and antagonistic effects in human MCF-7 breast cancer cells of flexible estrogen receptor modulators. 1678 91

Bis-[(p-methoxybenzyl)cyclopentadienyl] titanium dichloride, better known as Titanocene Y, is a newly synthesized transition metal-based anticancer drug. We studied the antitumor activity of Titanocene Y with concentrations of 2.1, 21 and 210 micromol/l against a freshly explanted human breast cancer, using an in-vitro soft agar cloning system. The sensitivity against Titanocene Y was highly remarkable in the breast cancer tumor in the full concentration range. Titanocene Y showed cell death induction at 2.1 micromol/l, well comparable to cisplatin, given at a concentration of 1.0 micromol/l. A further preclinical development of Titanocene Y was warranted and therefore an MCF-7 human breast cancer xenograft nonobese diabetic/severe combined immunodeficient mouse model was used. Titanocene Y was given for 21 days at 30 mg/kg/day (75% of the maximum tolerable dose of Titanocene Y), which resulted in the reduction of the tumor volume to around one-third, whereas no mouse was lost because of the surprisingly low toxicity of Titanocene Y.
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PMID:Antitumor activity of Titanocene Y against freshly explanted human breast tumor cells and in xenografted MCF-7 tumors in mice. 1726 64


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