2-甲氧基雌二醇的研究进展

目的 讨论2-甲氧基雌二醇(2-ME)在抗肿瘤作用中的研究进展.方法 通过试验及CNKI期刊全文数据库检索系统,以2-ME、抗癌活性和结构改造为关键词,检索2003-2010年2-ME抗肿瘤作用方面的相关文献.结果 2-甲氧基雌二醇是体内分泌的一种雌性激素,对雌激素受体的亲和力较低,而对多种肿瘤细胞具有抑制作用.结论 ...     

Synthesis and in vivo antitumor evaluation of 2-methoxyestradiol 3-phosphate, 17-phosphate, and 3,17-diphosphate

A prodrug strategy was investigated to address the problem of limited aqueous solubility and the resulting limited bioavailability of the antitumor agent 2-methoxyestradiol. The 3-phosphate, 17-phosphate, and 3,17-diphosphate of 2-methoxyestradiol were synthesized. 2-methoxyestradiol 3-phosphate was metabolized more efficiently to the parent compound in vivo than 2-methoxyestradiol 17-phosphate, and it was also more cytotoxic in cancer cell cultures than either the 17-phosphate or the 3,17-diphosphate. These results agree with the in vivo anticancer activity of 2-methoxyestradiol 3-phosphate in a mouse Lewis lung carcinoma experimental metastasis model as opposed to the 17-phosphate and 3,17-diphosphate, both of which were inactive. The in vivo antitumor activity of 2-methoxyestradiol 3-phosphate at a dose of 200 mg/kg per day was comparable to that of a maximally tolerated dose of cyclophosphamide.     

A phase Ib study of preoperative lapatinib, paclitaxel, and gemcitabine combination therapy in women with HER2 positive early breast cancer

We conducted a phase I trial to determine the feasible dose for lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor, with paclitaxel and gemcitabine as a neoadjuvant treatment in HER2 positive patients. In this phase I dose-escalation study, cohorts of 3-6 HER2-positive operable breast cancer patients received lapatinib (1,000 mg/day or 1,250 mg/day PO) with paclitaxel (80 mg/m(2)) and gemcitabine (1,000 or 1,200 mg/m(2)) on days 1 and 8 every 21 days to determine the tolerable dosages. Among 13 patients enrolled, 12 (stage III; n?=?11: stage II; n?=?1) completed treatment and one withdrew consent. The recommended doses were 1000-mg/day lapatinib, 80-mg/m(2) paclitaxel, and 1,000-mg/m(2) gemcitabine. One patient developed dose-limiting grade 3 hepatotoxicity; 3 experienced dose-limiting grade 4 neutropenia. No notable decline in left ventricle ejection fraction occurred. Eight patients achieved clinical partial response and four achieved clinical complete response (CR). Three patients (25%) achieved both tumor and nodal pathologic CR, 5 (42%) achieved tumor pathologic CR, and 6 (50%) underwent breast-conserving surgery. No relationship between lapatinib dose intensity and tumor response was apparent. Median follow-up was 16.2 (range, 6.5-20.7) months. Lapatinib plus paclitaxel and gemcitabine was tolerable with no overlapping toxicity.     

Pharmacokinetics and Pharmacodynamics of Phenethyl Isothiocyanate: Implications in Breast Cancer Prevention

Phenethyl isothiocyanate (PEITC)—a naturally occurring isothiocyanate in cruciferous vegetables—has been extensively studied as a chemopreventive agent in several preclinical species and in humans. Pharmacokinetic features of unchanged PEITC are (I) linear and first-order absorption, (II) high protein binding and capacity-limited tissue distribution, and (III) reversible metabolism and capacity-limited hepatic elimination. Membrane transport of PEITC is mediated by BCRP, multidrug resistance-associated protein (MRP) 1, and MRP2 transporters belonging to the ATP-binding-cassette (ABC) family. PEITC is metabolized by glutathione S-transferase (GST) in the liver, with the glutathione conjugate of PEITC undergoing further conversion to mercapturic acid by N-acetyl transferase in rats and humans. PEITC modulates the activity and expression of numerous phase I and phase II drug-metabolizing enzymes and can inhibit the metabolism of procarcinogens to form carcinogens and increase carcinogen elimination. In recent years, several in vitro and in vivo studies have elucidated molecular mechanisms underlying the pharmacodynamics of PEITC in breast cancer that include cancer cell apoptosis by upregulation of apoptotic genes, cell cycle arrest at G2/M phase by generation of reactive oxygen species and depletion of intracellular glutathione, downregulation of the estrogen receptor, decrease in sensitivity to estrogen, and inhibition of tumor metastasis. Inhibition of angiogenesis is one of the recently reported mechanisms of breast cancer prevention by PEITC. Complex pharmacokinetics and pharmacodynamics of PEITC necessitate a systems-biology approach in parallel with PK/PD modeling to develop PEITC as a therapeutic agent for treating cancers.     

In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol

Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzymes, cytochrome P450 (CYP) 1A1 and 1B1, with the phase II enzymes catechol-O-methyltransferase (COMT) and glutathione S-transferase P1 (GSTP1), all of which are expressed in breast tissue. We employed both gas and liquid chromatography with mass spectrometry to measure E(2), the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), as well as methoxyestrogens and estrogen-GSH conjugates. The oxidation of E(2) to 2-OHE(2) and 4-OHE(2) was exclusively regulated by CYP1A1 and 1B1, regardless of the presence or concentration of COMT and GSTP1. COMT generated two products, 2-methoxyestradiol and 2-hydroxy-3-methoxyestradiol, from 2-OHE(2) but only one product, 4-methoxyestradiol, from 4-OHE(2). Similarly, GSTP1 yielded two conjugates, 2-OHE(2)-1-SG and 2-OHE(2)-4-SG, from the corresponding quinone 2-hydroxyestradiol-quinone and one conjugate, 4-OHE(2)-2-SG, from 4-hydroxyestradiol-quinone. Using the experimental data, we developed a multicompartment kinetic model for the oxidative metabolism of the parent hormone E(2), which revealed significant differences in rate constants for its C-2 and C-4 metabolites. The results demonstrated a tightly regulated interaction of phase I and phase II enzymes, in which the latter decreased the concentration of catechol estrogens and estrogen quinones, thereby reducing the potential of these oxidative estrogen metabolites to induce DNA damage.     

Vandetanib: An overview of its clinical development in NSCLC and other tumors

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.     

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium

Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-na?ve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m² on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.     

A novel anti-pancreatic cancer agent, LY293111

Arachidonic acid is metabolized by two major pathways, cyclooxygenases and lipoxygenases. The metabolites catalyzed by these enzymes are important mediators of acute and chronic inflammation. Both enzymes and their metabolites are well recognized to be involved in cancer development and progress. It is well documented that inhibition of cyclooxygenase 2 (COX-2) activity decreases cancer incidence and inhibits tumor growth. It has also been reported that 5-lipoxygenase is involved in cancer cell survival and proliferation. 5-lipoxygenase metabolites including both 5-HETE and leukotriene (LT) B4 directly mediate cancer cell growth. Although 5-HETE receptors are still elusive, two LTB4 receptor subtypes (BLT1 and BLT2) have been characterized. Both 5-lipoxygenase and LTB4 receptors are upregulated in both pancreatic cancer and early pancreatic cancer lesions; hence, these proteins are potential targets for cancer treatment and prevention. Recent studies have shown that an orally stable leukotriene (LT) B4 receptor antagonist, LY293111, has a potent anti-pancreatic cancer effect. LY293111 inhibits pancreatic cancer growth, induces tumor cell apoptosis both in vitro and in vivo, and enhances the anti-pancreatic cancer effect of gemcitabine. LY293111 exhibits its anti-cancer effects through LTB4 receptors and peroxisome-proliferator activated receptor-gamma. A phase I clinical trial indicated that LY293111 is well tolerated by patients with no significant side-effects. LY293111 may be a valuable drug for treatment of pancreatic cancer, especially in combination with gemcitabine. A double-blinded, placebo-controlled phase II clinical trial with LY293111 is currently underway. This review summarizes the current research status of LY293111 as an anti-cancer agent with a focus on pancreatic cancer.     

Antiestrogen, trans-tamoxifen modulation of human breast cancer cell growth

To gain further insight into how estrogens modulate cell function, the effects of estrogen on cell proliferation were studied in human breast cancer cells. We examined the effects of estrogen on the proliferation of three human breast cancer cell lines that differed in their estrogen receptor contents. Ten nM estradiol markedly stimulated the proliferation of MCF-7 human breast cancer cells that contained high levels of estrogen receptor (1.15±0.03 pmole/mg protein) over that of control. In T47D cells that contained low levels of estrogen receptor (0.23±0.05 pmole/mg protein), Ten nM estrogen slightly stimulated the proliferation over that of control. MDA-MB-231 cells, that contained no detectable levels of estrogen receptors, had their growth unaffected by estrogen. These results showed their sensitivity to growth stimulation by estrogen correlated well with their estrogen receptor content. Also we examined the effect of estrogen on cellular progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. Ten nM estradiol showed maximal stimulation of progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. It is not clear whether these stimulations of progesterone receptor and plasminogen activator activity by estrogen are related to the estrogen stimulation of cell proliferation of MCF-7 cells. Studies with estrogen in human breast cancer cells in culture indicate that sensitivity to growth stimulation by estrogen correlates well with estrogen receptor contents.     

Pharmacological and clinical profile of exemestane (Aromasin), a novel irreversible aromatase inhibitor

Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.     

Estrogen modulation of human breast cancer cell growth

To gain further insight into how estrogens modulate cell function, the effects of estrogen on cell proliferation were studied in human breast cancer cells. We examined the effects of estrogen on the proliferation of three human breast cancer cell lines that differed in their estrogen receptor contents. Ten nM estradiol markedly stimulated the proliferation of MCF-7 human breast cancer cells that contained high levels of estrogen receptor (1.15+/-0.03 pmole/mg protein) over that of control. In T47D cells that contained low levels of estrogen receptor (0.23+/-0.05 pmole/mg protein), Ten nM estrogen slightly stimulated the proliferation over that of control. MDA-MB-231 cells, that contained no detectable levels of estrogen receptors, had their growth unaffected by estrogen. These results showed their sensitivity to growth stimulation by estrogen correlated well with their estrogen receptor content. Also we examined the effect of estrogen on cellular progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. Ten nM estradiol showed maximal stimulation of progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. It is not clear whether these stimulations of progesterone receptor and plasminogen activator activity by estrogen are related to the estrogen stimulation of cell proliferation of MCF-7 cells. Studies with estrogen in human breast cancer cells in culture indicate that sensitivity to growth stimulation by estrogen correlates well with estrogen receptor contents.     

A Phase I Trial of Daily Oral 4′-N-Benzoyl-Staurosporine in Combination with Protracted Continuous Infusion 5-Fluorouracil in Patients with Advanced Solid Malignancies

PURPOSE: 4'- N -Benzoyl-staurosporine (PKC412) is an orally available staurosporine derivative that inhibits protein kinase C. The objectives of this phase I trial were to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetics of PKC412 when co-administered with 5-Fluorouracil (5-FU). EXPERIMENTAL DESIGN: PKC412 was given daily with a 21-day continuous i.v. infusion of 5-FU 200 mg/m2/day, repeated every 4 weeks. The PKC412 dose was escalated by a modified continual reassessment method. The steady-state plasma pharmacokinetics of 5-FU, PKC412, and two of its circulating metabolites were determined during the first cycle of therapy. RESULTS: A total of 33 patients were treated with 70 cycles (median: 2, range: 1-4) of PKC412 at doses ranging from 25 to 225 mg/day. No significant toxicities were encountered with doses up to 150 mg/day. Among nine patients treated with 225 mg/day of PKC412, one experienced grade 3 fatigue and nausea, another developed grade 3 hyperglycemia, and three had grade 2 emesis and stomatitis, leading to early treatment discontinuation. Minor responses consisting of a 40-45% tumor reduction were observed in two patients, one with gall bladder carcinoma and one with breast cancer. Mean values of steady-state pharmacokinetic variables for both PKC412 and 5-FU were comparable to single agent studies. CONCLUSIONS: The recommended phase II dose of PKC412 is 150 mg/day when combined with a continuous infusion of 200 mg/m2/day 5-FU. The dose limiting toxicity was grade 2 emesis and stomatitis and the regimen showed indications of activity. There was no evidence of a pharmacokinetic interaction between the two drugs.     

Plasma protein binding of the investigational anticancer agent 2-methoxyestradiol

2-Methoxyestradiol (2ME2) is an endogenously produced metabolite of estradiol currently being tested in phase I and II clinical trials as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of 2ME2. The distribution of 2ME2 in plasma was studied in vitro using plasma from healthy human volunteers and ex vivo using plasma from patients with cancer receiving the drug orally. The equilibrium dialysis method used to characterize plasma protein binding of 2ME2 utilized a tracer amount of [H]-2-methoxyestradiol on a 96-well microdialysis plate with a 5-kDa cutoff membrane and 250 mul of plasma. The time to equilibrium was approximately 24 h and the mean unbound fraction of 2ME2 (fu) over the observed concentration range in plasma of patients receiving 2ME2 orally was 0.019+/-0.0043. The mean fu was 0.027+/-0.0019 in plasma of healthy human volunteers. The binding was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. The binding was also unaffected by the presence of 2-methoxyestrone, one of the major metabolites of 2ME2. 2ME2 was found to bind in decreasing order to plasma>albumin>alpha1-acid glycoprotein>sex-hormone-binding globulin. Plasma concentration-time profiles of total 2ME2 and unbound 2ME2 concentrations in a patient with cancer receiving 2ME2 as a single oral dose were parallel to each other. Thus, indicating that plasma protein binding is not an important consideration in pharmacokinetic monitoring of 2ME2.     

UFT in combination with oxaliplatin: clinical phase I study in patients with advanced or metastatic solid tumors

This phase I trial evaluated the combination of oxaliplatin plus UFT in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and the dose limiting-toxicity for future phase II trials. Eligible patients (N = 27) were treated in sequential cohorts of three to six patients. The starting doses for oxaliplatin and UFT were 70 mg/m2 and 250 mg/m2/day respectively, and five dose levels were designed up to 85 mg/m2 and 400 mg/m2/day. Oxaliplatin was administered i.v. on day 1 and 15, and oral UFT was given daily in three divided doses on days 1-21 followed by 1 week rest of a 28-day cycle. At the recommended dose, six additional patients were entered. In total, 79 courses were administered with a median of 3 (range 1-6). MTD was not reached; oxaliplatin 85 mg/m2 on day 1 and 15 plus UFT 400 mg/m2/day for 21 days was considered the optimum combination for phase II trials. Gastrointestinal toxicity and asthenia were the most common adverse events. Eight out of 13 patients (61.5%) with metastatic colorectal cancer achieved stable disease. UFT plus oxaliplatin is a feasible and safe combination. A phase II trial in first-line advanced colorectal cancer is ongoing.     

Toxicological studies on a new cephamycin, MT-141. V. Its subacute toxicity in beagle dogs

The 30-day subacute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) administrations of 100 to 1,200 mg/kg/day. The obtained results were as follows. MT-141 at the doses lower than 800 mg/kg/day i.v. had no toxicity in male and female Beagle dogs. An increase in water intake was closely related to that in urine excretion after i.v. treatments with 1,200 mg/kg/day of MT-141 in the males and females. MT-141 at the doses higher than 1,000 mg/kg/day i.v. of MT-141 caused slight local irritation at the site of injection in the males and females. In the females, the dose-dependent changes induced by treatments with the doses above 1,000 mg/kg/day i.v. of MT-141 were a significant decrease in the level of serum K and a significant increase in the activity of serum LAP. In the males, this compound produced significant dose-dependent changes in toxicological parameters such as a decrease in the activity of GOT at the doses higher than 1,000 mg/kg/day i.v., a descent in the levels of U-K, U-Cl and OP at the dose of 1,200 mg/kg/day i.v., an elevation in the level of serum alpha 1- and alpha 2-G, and an increase in the volume of excreted urine at the dose of 1,200 mg/kg/day i.v. It is concluded from the above-mentioned results that the maximal "no effective" dose of MT-141 is 800 mg/kg/day i.v. and the toxic dose of MT-141 is above 1,000 mg/kg/day i.v. in male and female Beagle dogs.     

多靶点抗肿瘤新药索拉非尼的研究进展

索拉非尼是一种口服多激酶抑制药,靶向作用于肿瘤细胞和肿瘤血管丝氨酸和(或)苏氨酸及受体酪氨酸激酶,具有抑制肿瘤细胞增殖和血管形成的双重作用。Ⅰ期临床的推荐剂量为400mg,每日两次。Ⅱ及Ⅲ期临床实验表明索拉非尼对肾癌、肝癌、黑素瘤和非小细胞肺癌都有一定的治疗作用。FDA已批准索拉非尼用于肾癌、肝癌的治疗。     

Estrogenic activity and estrogen receptor beta binding of the UV filter 3-benzylidene camphor. Comparison with 4-methylbenzylidene camphor

UV filters represent new classes of estrogenic [Environ. Health Perspect. 109 (2001) 239] or antiandrogenic [Toxicol. Sci. 74 (2003) 43] chemicals. We tested 3-benzylidene camphor (3-BC), reported as estrogenic in fish [Pharmacol. Toxicol. 91 (2002) 204], and mammalian systems in comparison to 4-methylbenzylidene camphor (4-MBC), shown to be active in rats, and analyzed binding to estrogen receptor subtypes. 3-BC and 4-MBC stimulated MCF-7 cell proliferation (EC(50): 0.68 and 3.9 microM). The uterotrophic assay of 3-BC (oral gavage) in immature rats showed unexpected potency with ED50 45.3mg/kg per day; lowest effective dose 2mg/kg per day, and maximum effect with 70% of ethinylestradiol. After comparing with literature data, we found that the oral 3-BC was considerably more potent than oral bisphenol A and almost as active as subcutaneous genistein. 3-BC and 4-MBC displaced 16alpha 125I-estradiol from porcine uterine cytosolic receptors (IC(50): 14.5 and 112 microM), and from recombinant human estrogen receptor beta (hERbeta) (IC(50): 3-BC, 11.8 microM; 4-MBC, 35.3 microM), whereas no displacement was detected at human estrogen receptor alpha (hERalpha) up to 3mM. This subtype selectivity makes the two camphor derivatives interesting model compounds. Their activity on immature rat uterus is not easily explained by ERbeta activation. It cannot be excluded that active metabolites with possibly different receptor binding characteristics are formed in vivo.