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PubMed2000

Lack of evidence for tamoxifen- and toremifene-DNA adducts in lymphocytes of treated patients.

Tamoxifen (TAM) is used for the adjuvant treatment of women with breast cancer and has also been recommended as a chemopreventive agent. Among unwanted side effects, TAM was shown to increase endometrial cancer in treated women by mechanisms that are not yet clearly understood. We studied DNA adducts in lymphocytes of female breast cancer patients treated with TAM or toremifene (TOR), a TAM analogue and compared them with adducts formed by TAM in rat liver, where the drug induces tumours. DNA adducts were measured by TLC-(32)P-post-labelling assays. After TLC, all DNA samples including DNA from untreated healthy women showed a faint radioactive zone, where the positive control DNA adducts isolated from the liver of rats treated with TAM migrated. The relative adduct levels were calculated from the radioactivity present in this zone. Means +/- SD of adduct levels per 10(8) nucleotides (associated with this area) were for untreated volunteers (control) 1.83 +/- 1.41 (n = 13), for TAM treatment 2.17 +/- 3.04 (n = 25) and for TOR treatment 1.18 +/- 1.05 (n = 8). Most of the human samples were further analysed by HPLC after labelling with (32)P in order to compare adducts in human DNA with those in liver DNA isolated from TAM-treated rats. None of the human samples showed any peaks at retention times where putative TAM-DNA adducts were eluted. In conclusion, lymphocyte DNA from female patients treated at therapeutic levels did not show evidence of the formation of TAM- or TOR-DNA adducts.

Adult↗
PubMed1987

Effect of a rhodium complex on alterations of hepatic function in thioacetamide-induced hyperplastic noduligenesis in rats.

An in vivo model of liver hyperplastic noduligenesis was induced in rats by long-term administration of thioacetamide (TAM) (50 mg/kg/day i.p.). Three doses of 50 mg/kg of an antitumoral Rh(III) complex were administered at 14, 9 and 5 days before the end of TAM treatment. Plasma and urine were obtained from either TAM or Rh(III) complex or TAM plus Rh(III) complex treated rats to determine the interactions of both substances with the biochemical parameters related to liver function. The rise in alkaline phosphatase (ALP), leucine aminopeptidase (LAP), gamma-glutamyl transferase (GGT) and the unchanged activities in the aspartate and alanine aminotransferases (AST, ALT) in plasma of TAM-treated rats indicated that the disease induced by this substance can be considered as a chronic obstructive biliary disease with indices of cell proliferation and tumors. The increased concentration of bilirubin both in the plasma and urine of TAM-treated rats suggested liver cholestasis and hepatobiliary obstruction. The very low values of creatinine clearance indicated that there was some degree of kidney failure due to the effect of TAM. The increased concentration of ammonia both in plasma and urine were probably a consequence of the decreased flux in the urea cycle in the liver. The Rh(III) complex alone did not produce significant changes in the plasma enzyme activities. The only significant changes were found in the concentrations of uric acid and ammonia in the urine. When the Rh(III) complex was administered to TAM-treated rats, significant restoration of the following parameters were observed: plasma enzymatic activities, blood bilirubin and ammonia, uric acid and creatinine in the urine and the creatinine clearance. These results suggest that the altered liver function induced by TAM can be restored by Rh(III) complex. The mechanisms by which this complex acts to counteract the TAM-induced changes are not yet established.

Acetamides↗
PubMed1991

Structural requirements for the in vitro transformation of Syrian hamster embryo cells by stilbene estrogens and triphenylethylene-type antiestrogens.

The mechanisms of estrogen-induced cancer are still a matter of debate. Previous studies with stilbene estrogens and steroidal estrogens have shown that the in vitro transformation of primary Syrian hamster embryo (SHE) fibroblasts is a good experimental system for discriminating hormonal from nonhormonal events. We have now extended these studies to the triphenylethylene-type antiestrogens tamoxifen (TAM), 3-hydroxy-TAM, 4-hydroxy-TAM and 3,4-dihydroxy-TAM. Furthermore, a structural isomer of diethylstilbestrol (DES) with the hydroxy groups shifted into the meta-positions (3,3'-DES) was included. Our data clearly show that TAM and 4-hydroxy-TAM give rise to morphologic and neoplastic transformation of SHE cells in culture. In contrast, neither 3-hydroxy-TAM nor 3,3'-DES led to a significant transformation, in spite of the fact that both compounds are hormonally active. These results support the notion that nonhormonal events are essential for SHE cell transformation and suggest certain structural features to be necessary for the transforming capability. The putative carcinogenicity of TAM and 4-hydroxy-TAM but not of 3-hydroxy-TAM, as implied by these in vitro transformation studies, is corroborated by recent reports on ovarian and Leydig cell tumors in mice and hepatocellular carcinomas in rats.

Animals↗
PubMed2005

Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin.

Tamoxifen (TAM), used as the endocrine therapy of choice for breast cancer, undergoes metabolism primarily forming N-desmethyltamoxifen, 4-hydroxytamoxifen, alpha-hydroxytamoxifen, and tamoxifen-N-oxide (TNO). Our earlier studies demonstrated that flavin-containing monooxygenases (FMOs) catalyze the formation of TNO. The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM. CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 all reduced TNO, with CYP2A6, CYP1A1, and CYP3A4 producing the greatest reduction. A portion of TAM formed by CYP3A4-mediated reduction of TNO was further metabolized, but not TAM formed by the other P450s. TNO reduction by P450s is extremely rapid with considerable TAM formation detected at the earliest time point that products could be measured. TAM formation exhibited a lack of linearity with incubation time but increased linearly as a function of TNO and P450 concentration. TNO was converted into TAM by reduced hemoglobin (Hb) and NADPH-P450 oxidoreductase, suggesting involvement of the same heme-Fe(2+) complex in both Hb and P450s. The findings raise the question of whether the reductive activity may be nonenzymatic. Results of this in vitro study demonstrate the potential of TAM and TNO to be interconverted metabolically. FMO seems to be the major enzymatic oxidant, whereas several P450 enzymes and even reduced hemoglobin are capable of reducing TNO back to TAM. The possibility that these processes may comprise a metabolic cycle in vivo is discussed in this article.

Cytochrome P-450 Enzyme System↗
PubMed2004

Long-term exposure to tamoxifen induces hypersensitivity to estradiol.

In women with hormone-dependent breast cancer, tamoxifen (TAM) frequently induces tumor regression, but regrowth occurs with continuation of antiestrogen therapy. Studies of breast xenografts in nude mice suggest that this secondary resistance to TAM may reflect the development of enhanced sensitivity to the estrogenic properties of TAM. In the current study, we examined the hypothesis that TAM could also induce a state of hypersensitivity to estradiol (E(2)) itself. Oophorectomized nude mice with MCF-7 cell xenografts received 25-mg implants of TAM [long-term TAM treated (LTTT) mice] or cholesterol (C-MCF-7) over a 5-month period (phase 1). The LTTT group regressed to a lesser extent than did C-MCF-7 tumors. After 4 months of TAM exposure, the LTTT tumors begin to regrow, as did the C-MCF-7, as assessed by slope analysis. At 5 months, TAM or vehicle implants were removed, and the LTTT and C-MCF-7 subgroups were given vehicle or two doses of E(2) to test estrogen sensitivity (phase 2). We used our "E(2) clamp" technique to maintain levels of plasma E(2) at either 1.25 or 20 pg/ml. Neither group responded to the very low concentrations of E(2) (1.25 pg/ml) or vehicle. The LTTT tumors but not C-MCF-7 tumors exhibited a growth response on exposure to 20 pg/ml E(2) during 7 weeks, as demonstrated with mixed models analysis. These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E(2) itself.

Animals↗
PubMed1992

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

PURPOSE: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). PATIENTS AND METHODS: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. RESULTS: The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. CONCLUSION: The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.

Adult↗
PubMed2004

Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial.

PURPOSE: To assess whether an epirubicin (EPI) -based chemotherapy plus hormonal regimen improves disease-free (DFS) in women older than 65 years, with node-positive, operable breast cancer (BC), relative to tamoxifen (TAM) alone. PATIENTS AND METHODS: A total of 338 patients were randomly assigned after surgery to receive TAM 30 mg/d for 3 years (TAM, n = 164), or EPI 30 mg on days 1, 8, and 15 every 28 days for six cycles plus TAM 30 mg/d for 3 years (EPI-TAM, n = 174). In both arms, patients received radiotherapy, delivered after chemotherapy (CT) in the EPI-TAM group. RESULTS: The 6-year DFS rates were 69.3% with TAM and 72.6% with EPI-TAM (P = .14). The multivariate analysis shows a relative risk of relapse of 1.93 (95% CI, 1.70 to 2.17) with TAM compared with EPI-TAM (P = .005). The 6-year OS, related to disease progression, was 79.1% and 79.8%, respectively (P = .41). Compliance with CT was good: 96.9% of patients received six cycles. The acute toxicity per patient was mild: grade 2 neutropenia in 5.9%, grade 2 anemia in 2.0%, grade 3 nausea or vomiting in 4.6%, and grade 3 alopecia in 7.2%. Five cases (in five patients) of decreased left ventricular ejection fraction occurred after CT: three after adjuvant CT, and two after anthracycline-based CT for relapse. One patient died as a result of dysrhythmia related to carcinomatous lymphangitis. No secondary leukemia occurred. CONCLUSION: This study conducted in node-positive elderly patients demonstrates a significant contribution of a weekly EPI regimen in terms of DFS. Moreover, this regimen is safe for hematologic, nonhematologic, and cardiac toxicities.

Age Factors↗
PubMed2004

Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer.

PURPOSE: Tamoxifen (TAM) is thought to exert a cytostatic effect on hormone-sensitive breast cancer cells. Some preclinical studies show reduced radiosensitivity in irradiated malignant mammary epithelial cells when pretreated with TAM; other studies refute these results. Recent randomized clinical trials suggest an antagonistic effect of TAM on cytotoxic therapy, with improved disease-free survival (DFS) with sequential versus concurrent TAM. An exploratory analysis was undertaken to evaluate the optimal sequencing of TAM and radiotherapy (RT) after breast-conserving surgery. PATIENTS AND METHODS: Southwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF --> TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF --> TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size. RESULTS: With a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54). CONCLUSION: The current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.

Aged↗
PubMed1986

Estrogen and progesterone receptors in the fetal and newborn vagina of guinea pig: biological, morphological, and ultrastructural responses to tamoxifen and estradiol.

Estrogen and progesterone receptors were characterized in the fetal and newborn vagina of guinea pig. The concentrations of estrogen receptor (total sites, cytosol plus nuclei) which were very high [7090 +/- 1700 (+/- SD) fmol/mg DNA] in the fetal vagina (62-64 days gestation) decreased significantly after birth and increased slightly at 2 weeks of age. Tamoxifen (TAM) and estradiol (E2) or the combined treatment (TAM + E2) induced a great increase in weight and DNA content in both the fetal and newborn vagina. After a 12-day treatment to pregnant or newborn guinea pigs, the fetal vagina wet weights (milligrams +/- SD) were as follows: control animals, 87 +/- 14; +TAM, 254 +/- 38; +E2, 177 +/- 19; +(TAM+E2), 218 +/- 41. The values in newborn vaginas were: 155 +/- 40, 434 +/- 75, 477 +/- 49, and 512 +/- 76, respectively. The DNA contents per vagina (in micrograms per +/- SD) in the fetal tissues were as follows: control, 187 +/- 64; +TAM, 563 +/- 74; +E2, 650 +/- 100; and +(TAM+E2), 776 +/- 113; in the newborn vagina these values were: 592 +/- 75, 880 +/- 113; 781 +/- 75, and 901 +/- 15, respectively. Histological studies showed drastic morphological alterations after each of the treatments, particularly in the epithelial cells. Similarly, the ultrastructural examination with transmission electron microscopy showed the alteration of mitochondria, the development of the rough endoplasmic reticulum, and the formation of numerous vacuoles and secretory granules. TAM stimulated the number of specific sites for progesterone, but less intensely than did E2. However, in the combined experiment (TAM+E2), TAM did not block the action of E2. It is concluded that TAM acts in the fetal and newborn vagina of guinea pigs as a real estrogen agonist.

Animals↗
PubMed2003

Effects of water temperature and substrate type on spore production and release in eastern Tubifex tubifex worms infected with Myxobolus cerebralis.

Eastern Tubifex tubifex worms were exposed to Myxobolus cerebralis spores at 9, 13, 17, and 20 C in 1-L jars that contained sand, mud, or leaf litter as substrata. Beginning 60 days after exposure, water from each jar was filtered daily and examined for the presence of waterborne triactinomyxon spores (TAMs). On discovering a single TAM from an experimental jar, 48 T. tubifex worms from that jar were placed individually into 24-well plates. Spores released from individual infected T. tubifex worms were quantified to determine the first day of TAM release from infected worms, the infection rate, the total number of TAMs released per worm, and the duration of release. No TAMs were found in any of the jars incubated at 20 C or in uninfected, control worms at any temperature. The total number of TAMs released by infected worms in mud and sand was highest at 13 C compared with other temperatures. Infection rates among individual worms increased with temperature between 9 and 17 C. Higher temperatures (up to 17 C) induced earlier TAM releases among infected worms, and substratum did not influence this production parameter. The average duration of TAM release decreased as the temperature increased from 9 to 17 C, and there was a significant effect of substratum in the groups maintained at 13 and 17 C. In all temperature treatments between 9 and 17 C, the duration of release was least in the worms maintained in leaf litter, as was the total number of TAMs released during the experimental period and the median number of TAMs per production day.

Animals↗
PubMed1999

Mutagenic potential of alpha-(N2-deoxyguanosinyl)tamoxifen lesions, the major DNA adducts detected in endometrial tissues of patients treated with tamoxifen.

Breast cancer patients treated with the antiestrogen tamoxifen (TAM) show an increased risk of developing endometrial cancer. We have recently detected TAM-DNA adducts in endometrium obtained from patients treated with TAM and identified them as trans- and cis-forms of alpha-(N2-deoxyguanosinyl)tamoxifen (dG-N2-TAM). To explore the mutagenic properties of these TAM-DNA adducts, we prepared site-specifically modified oligodeoxynucleotides containing a single isomer of dG-N2-TAM by reacting a 15-mer oligodeoxynucleotide containing a single dG (5'-TCCTCCTCGCCTCTC) with tamoxifen alpha-sulfate. These modified oligodeoxynucleotides were inserted into a single-stranded shuttle vector to investigate mutagenic specificities of the adducts in simian kidney (COS-7) cells. An epimer of dG-N2-trans-TAM showed targeted mutations ranging from 0.7 to 1.5%. The other dG-N2-trans-TAM adduct showed 9.6% G-->T transversions, accompanied by 2.8% G-->A transitions. Both dG-N2-cis-TAM adducts showed similar mutation spectra, where G-->T transversions (11-12%) predominated, along with a small number of G-->A transitions and G-->C transversions. Thus, dG-N2-TAMs are mutagenic lesions in mammalian cells. The tamoxifen-DNA adducts detected in patient endometrium may cause mutations and initiate endometrial cancer.

Animals↗
PubMed1999

Endometrial cancer after tamoxifen treatment of breast cancer. Results of a retrospective cohort study.

PURPOSE: The aim of the present retrospective study was to evaluate the relationship between the use of Tamoxifen (TAM) and development of endometrial carcinoma (EC) in Slovenia women patients (pts). METHODS. This retrospective study included 408 pts, aged 55 years or more, treated for invasive breast cancer (285 pts were treated with TAM, 123 pts without it) at our Institute from 1988 to 1992. The pts who had had hysterectomy were not included. The observation period was 5 to 9 years. The Mantel-Haenszel chi2 test and Fisher p test were used. Survival was computed by Kaplan-Meier estimates. RESULTS: As to the most common risk factors of EC no statistically significant difference was observed. The daily dose of TAM was 20 mg, median treatment period was 38 months (1-97). In 15% of pts, TAM-related side-effects were noted 30 months later; the most common was uterine bleeding. EC was detected in 10/30 pts with curettage, while others had polypous changes and cystic hyperplasia. In the group of pts without TAM, curettage was performed in 4 pts. In view of curettage, the difference between the two groups was statistically significant (p=0.014). In the group of pts without TAM, EC was detected in 2 pts. Evaluated relative risk (RR) was 2.16 (0.48-9.70). Between the TAM groups of pts with and without EC, the difference in survival was minimal, statistically nonsignificant (p=0.41). CONCLUSION: Treatment with TAM increases the risk of benign endometrial changes and EC. In EC cases treatment with TAM does not influence the pts survival. Pts using TAM need to know what symptoms and signs should be reported.

Aged↗
PubMed2000

Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells.

Tamoxifen (TAM) is widely used in the treatment of breast cancer. The cytostatic effects of TAM have been attributed to the antagonism of estrogen receptor (ER) and inhibition of estrogen-dependent proliferative events. However, the mechanism by which TAM is also effective against certain ER-negative breast tumors remains to be elucidated. Here we report that TAM induced the activity of caspase-3-like proteases in ER-negative breast cancer cell lines MDA-MB-231 and BT-20, as evidenced by the cleavage of fluorogenic tetrapeptide substrate and of poly(ADP-ribose) polymerase. The activation of caspase-3-like proteases preceded TAM-induced chromatin condensation and nuclear fragmentation, the typical apoptotic morphologies. Pretreatment of cells with a specific inhibitor of caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde, or with a general inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, prevented TAM-induced apoptosis. TAM also stimulated c-Jun NH2-terminal kinase (JNK) 1 activity, and interfering with the JNK pathway by over-expressing a DN JNK1 mutant attenuated TAM-induced apoptosis. In addition, treatment of cells with a lipid-soluble antioxidant vitamin E blocked TAM-induced caspase-3 and JNK1 activation as well as apoptosis, whereas water-soluble antioxidants N-acetyl L-cysteine and glutathione had little effect. Thus, this study demonstrates that TAM induces apoptosis in ER-negative breast cancer cells through caspase-3 and JNK1 pathways, which are probably initiated at the cell membrane by an oxidative mechanism.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Tamoxifen modulates apoptotic pathways in primary endometrial cell cultures.

Clinical data indicate that tamoxifen (TAM) therapy may cause an increased risk of endometrial pathology in postmenopausal but not in premenopausal women. Molecular mechanisms of the uterotrophic activity of TAM have not been clearly established nor its relevance to apoptosis in endometrial cells. The present study was implemented to evaluate the apoptotic effect of TAM on primary endometrial cell cultures in the presence or absence of steroid hormones (SHs). A total of 14 primary endometrial cell cultures were established and maintained both with and without SHs. Cell cultures were treated for 24 h with either 20 microM TAM or 10 nM estradiol. Apoptotic cells presented in a pre-G1 peak and the expression of bcl-2 were studied using flow cytometry. All endometrial cell cultures maintained in a SH-containing environment, except one, responded to TAM by a significant increase (P = 0.03) in the pre-G1 cell fraction, indicating a proapoptotic effect. A significant (P = 0.03) reduction in the pre-G1 peak equivalent to an antiapoptotic response was observed in 6 of 13 cell cultures maintained in a SH-deficient environment. In 4 of 10 cell cultures evaluated in both media, the pre-G1 population was medium dependent. In 8 of 10 cultures evaluated for Bcl2 levels, no trend was found in either media, but a dependency on SH content was observed. Comparison between effects of TAM and estradiol demonstrated identical trends, regardless of the menstrual phase or SH content in cell environments. These results suggest that TAM acts as an estrogen agonist on endometrial tissue in both environments. We conclude that TAM modulates apoptotic pathways in primary endometrial cell cultures. The SH content in the cell environment influences the apoptotic effect of TAM and determines the propensity for a cell to undergo apoptosis or, on the contrary, to resist apoptotic death in response to TAM treatment. This is in concordance with the observed clinical risk of endometrial pathologies in postmenopausal versus premenopausal women.

Adult↗
PubMed2001

Tamoxifen modulates the expression of Ki67, apoptosis, and microvessel density in cervical cancer.

PURPOSE: The aim of the study was to investigate if a short-term administration of high-dose Tamoxifen (Tam) could affect the expression of biologically relevant biochemical parameters in cervical cancer tissue. EXPERIMENTAL DESIGN: The study was conducted in 24 patients with histologically confirmed cervical tumors. Biopsies were obtained by colposcopy on day 0 in all patients, who then received either 80 mg/die or 160 mg/die for 5 consecutive days until the second biopsy was obtained. Immunohistochemistry was performed with antiestrogen receptor (ER), anti-Ki67, anticaspase cleavage product of keratin 18 (M30), and anti-CD31 monoclonal antibodies. RESULTS: Eleven (45.8%) of 24 cervical tumors were ER positive. The percentage of Ki67-positive tumor cells in pre-Tam biopsies was significantly higher than the percentage in the corresponding posttreatment biopsies (z = 4.29, P = 0.0001). No difference in the pretreatment percentage of Ki67-positive cells according to ER status was found. The percentage of M30 positivity was higher in post-Tam than in pre-Tam biopsies. Microvessel density values in pre-Tam biopsies were significantly higher than corresponding values in posttreatment tissues (z = -3.72, P = 0.0002). The reduction in the percentage of Ki67-positive tumors was significantly (z = 3.58, P = 0.0003) higher in ER-positive than in ER-negative tumors, whereas no difference in Tam-induced reduction of microvessel density values according to ER status (z = -0.18, P = 0.85) was found. Tam treatment did not induce any change of M30 positivity in ER-positive tumors, whereas in ER-negative tumors, it produced a significant (P = 0.015) increase in the percentage of M30-positive cells in post-Tam versus pre-Tam biopsies. CONCLUSIONS: A short-term treatment with Tam at doses 4-8-fold higher than those in conventional schemes is associated with modifications of biological parameters associated with tumor cell proliferation, apoptosis, and neoangiogenesis in cervical cancer.

Adult↗
PubMedDate not supplied

Role of tumor-associated macrophages in renal cell carcinoma.

We investigated the biologic meaning of tumor-associated macrophages (TAM) in renal cell carcinoma (RCC). The study group comprised of 83 patients with RCC. TAM was isolated by plastic adherence following enzymatic digestion of surgically removed tumor tissues. In some of the patients, monocytes were also isolated from peripheral blood mononuclear cells by plastic adherence. When TAM and monocytes were compared in the same patients, TAM produced interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) without lipopolysaccharide (LPS) stimulation, while monocytes hardly produced IL-6, TNFalpha and IL-1beta without LPS stimulation. However, with LPS stimulation, monocytes produced more IL-6, TNFalpha and IL-1beta than TAM. In stage T1 RCC patients, there was a significant positive correlation between TNFalpha production of TAM and tumor size. In order to investigate the effects of TAM on cancer cells, TAM was co-cultured with A498, K562 and in some cases, with short-term established RCC lines for 96 h. As a result, TAM largely enhanced cell proliferation. These results suggested that TAM may play an important role in certain steps of tumor progression.

Carcinoma, Renal Cell↗
PubMed2003

Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.

Animals↗
PubMed2005

Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density.

Stromal cells, within and around the tumor, as well as tumor cells are both involved in angiogenesis which is an important step in tumor growth and metastasis. Among such stromal cells, macrophages are known to play various roles in tumor angiogenesis and have thus been called tumor-associated macrophages (TAMs). The TAM density, vascular endothelial growth factor (VEGF) expression and the microvessel density (MVD) were immunohistochemically evaluated in 249 paraffin-embedded sections of invasive ductal carcinoma of the breast. The TAM density and MVD were assessed as the average density of three hot spots at a magnification of x400 and x200, respectively. The TAM density showed a significant correlation with both the VEGF expression and MVD, while a significant correlation was also found between the VEGF expression and MVD. The TAM density was also associated with the nuclear grade, estrogen receptor status and MIB-1 count. Patients with a high TAM density had a significantly (p=0.0025) worse disease-free survival (DFS) prognosis than those with a low TAM density, while univariate analyses also indicated both the MVD (p<0.0001) and VEGF expression (p=0.0152) to be prognostic factors for DFS. A multivariate analysis indicated MVD (p=0.0057), as well as lymph node metastasis and the MIB-1 count, to be independently significant prognostic factors for DFS. In conclusion, the present study demonstrated a close association between TAM infiltration and both the VEGF expression and MVD. The prognostic significance of MVD was the strongest among these three factors in breast cancer. These findings suggested that the prognostic implications of TAM infiltration are due to the involvement of TAMs in tumor angiogenesis.

Adult↗