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PubMed2000

Tamoxifen-induced cell death in malignant melanoma cells: possible involvement of the insulin-like growth factor-1 (IGF-1) pathway.

Recent data indicate that the estrogen receptor (ER) blocker tamoxifen (TAM) can induce cell death in malignant melanoma cells. However, as shown in the present study and several other studies melanoma cells usually do not express classical ERs. In the present study we investigated whether the cytotoxic effect of TAM on melanoma cells could depend on interference with the expression or function of the insulin-like growth factor-1 receptor (IGF-1R), a plasma membrane receptor important for cell survival in this tumor cell type. Several melanoma cell lines were included in the analysis. Administration of TAM at a concentration of 15 microm or more resulted in cell death of the melanoma cells within 48 h. TAM treatment was correlated to a slight to moderate inhibition of IGF-1 binding to IGF-1R. Since it has been reported that TAM can increase the release of IGF binding proteins (IGFBPs) we then investigated whether this mechanism could underly the decreased IGF-1 binding. However, we could demonstrate that the amount of released IGFBPs were unchanged or decreased in TAM-treated cells. Whereas TAM did not have any strong effect on IGF-1 binding and the expression of IGF-1R at the cell surface, it was was found to efficently block tyrosine phosphorylation of IGF-1R beta-subunit. Taken together, our data suggest that TAM-induced cytotoxicity of malignant melanoma cells can be due to inactivation of IGF-1R.

Antineoplastic Agents, Hormonal↗
PubMed1998

Effects of tamoxifen on nitric oxide synthesis and neoplastic transformation in C3H 10T1/2 fibroblasts.

Tamoxifen (TAM) is used in the prevention and treatment of breast cancer, however, its mechanisms of therapeutic action as well as its pathologic effects are not fully understood. We report that TAM (10(-7)-10(-5) M) inhibits 3-methylcholanthrene-induced transformation of C3H 10T1/2 murine fibroblasts in a dose-responsive manner. Over this concentration range, TAM (>10(-6) M) potentiates inducible nitric oxide synthase (iNOS) activity in 10T1/2 cells. This increase in NO synthase activity was mediated through an increase in iNOS protein for cells stimulated with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS). Significant increases in NO formation were observed when TAM (10(-5)) was added prior to or simultaneously with IFN-gamma/LPS treatment, whereas the addition of TAM 48 h after IFN-gamma/LPS treatment had no effect on NO synthesis. The morphologic changes seen with cells treated with TAM are similar to those observed in cells treated with TGF-beta1. TGF-beta1 inhibited NO production at high doses and slightly enhanced NO formation at low doses in IFN-gamma/LPS-stimulated cells. The transformation inhibitory effects of TAM did not appear to be related to the effects on cellular proliferation of neoplastic cells as TAM did not inhibit the growth of neoplastic cells into foci in the presence of normal confluent C3H 10T1/2 fibroblasts.

Animals↗
PubMed1999

Involvement of Ca2+ influx in the mechanism of tamoxifen-induced apoptosis in HepG2 human hepatoblastoma cells.

The signaling mechanism of tamoxifen (TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor (ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca2+. This effect was completely inhibited by the extracellular Ca2+ chelation with EGTA. TAM also induced a Mn2+ influx, indicating that TAM activated Ca2+ influx pathways. This action of TAM was significantly inhibited by flufenamic acid (FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca2+ chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca2+ signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells.

Apoptosis↗
PubMedDate not supplied

Tamoxifen induces ultrastructural alterations in membranes of Bacillus Stearothermophilus.

Tamoxifen (TAM), a non-steroid antiestrogen, is the mostly used drug for chemotherapy and chemoprevention of breast cancer. However, the mechanisms by which TAM inhibits cell proliferation in breast cancer are not fully understood. TAM strongly incorporates in biomembranes and a variety of effects have been assigned to biophysical and biochemical interactions with membranes. Therefore, a better understanding of the physicochemical basis of interaction of TAM with biomembranes is essential to elucidate the molecular mechanisms of action. A strain of Bacillus stearothermophilus has been used as a model to clarify the interaction of TAM with the cell membrane. TAM effects on the ultrastructure of membranes of this bacterium were evaluated by electron microscopy. Important ultrastructural alterations were observed in B. stearothermophilus treated with TAM, namely change in the geometry of the membrane profile from asymmetric to symmetric, disaggregation of ribosomes, coagulation of the cytoplasmic matrix, occurrence of mesossomes, appearance of fractures in membranes and the alteration of the ultrastructure of cell wall. These ultrastructural alterations confirm that TAM is a membrane-active drug and that membrane damage may be involved in molecular mechanisms of cell death induced by this drug.

Dose-Response Relationship, Drug↗
PubMed1998

Effects of partial versus pure antiestrogens on ovulation and the pituitary-ovarian axis in the rat.

The present study was undertaken to compare the effects of the pure antiestrogen ZM 182780 (ZM) and the partial agonist tamoxifen (TAM) on ovulation and peripheral hormone levels in the rat. Adult female rats were treated with ZM (5 mg/kg/d) or TAM (5 mg/kg/d) and sacrificed at varying times during the estrous cycle. ZM and TAM were able to inhibit ovulation to nearly the same extent (60% and 70%, respectively). ZM induced a persistent diestrus whereas TAM led to a mixed picture in the vaginal smear. Both antiestrogens suppressed the preovulatory surge of LH, FSH and progesterone but had no effect on basal FSH values. In contrast to TAM, ZM caused an increase in basal levels of LH. Moreover, basal and preovulatory levels of estradiol and androgens were increased by ZM. By contrast, TAM decreased basal and preovulatory values of LH, estradiol, and androgens. These data suggest that ZM inhibits not only the positive but also negative feedback effect of estrogens and TAM seems to inhibit only the positive feedback. Moreover, it is conceivable that the suppressed preovulatory progesterone surge induced by ZM and TAM could be responsible for the antiovulatory effect.

Animals↗
PubMed1998

Tamoxifen and carboplatin combinational treatment of high-grade gliomas. Results of a clinical trial on newly diagnosed patients.

Between April, 1992 and December, 1995, forty consecutive patients with a cerebral malignant glioma (WHO Grade III and IV) were enrolled in a trial consisting in surgery and post-operative administration of radiotherapy (4500-6000 cGy), carboplatin (CBDCA; dose of 450-600 mg/m2), and oral tamoxifen (TAM; at doses of 40, 80 or 120 mg/day). Two patients of the TAM group died in the postoperative period from a pulmonary embolism and myocardial infarction, respectively. The patients (all dosages combined) had a median survival time of 13 months from the time of diagnosis. The 12-month and 24-month survival rates were 52% and 32%, respectively. The median relapse-free survival time was 7 months. Patients treated with higher doses of TAM (80-120 mg/day) demonstrated a longer median survival rate (13 months both) and a longer 12-month survival result (58% and 76%, respectively). Patients who assumed TAM for a period longer than 3 months (group +3) have a higher median survival rate (16 months) and better 12-month and 24-month results (62% and 40%, respectively). Moreover, the median relapse-free survival time was 10 months (versus 6 months in group -3; p = 0.0038). However, it is not possible to exclude that patients of group +3 had a slower growing or a stable tumor and were well enough to assume TAM for a longer period. The results observed in the TAM-group have been compared with those of 40 matched controls treated with surgery, radiotherapy and CBDCA. These patients had a median survival time of 9 months (p = 0.04) and the 12-month and 24-month survival rates were 30% and 0%, respectively. The median relapse-free survival time was 4 months (p = 0.0014). These data suggest a potential role for combinational TAM-CBDCA therapy in the post-operative treatment of cerebral malignant gliomas; further clinical phase III trials, especially those with higher dosages of TAM are warranted.

Administration, Oral↗
PubMed2003

Sequential changes in serum triglyceride levels during adjuvant tamoxifen therapy in breast cancer patients and the effect of dose reduction.

Tamoxifen (TAM) and estrogen increase serum triglyceride (TG) levels, sometimes inducing severe hypertriglyceridemia and possibly contributing to death. Decreasing the dose of estrogen in estrogen replacement therapy may minimize its adverse effects, including the hypertriglyceridemia. The serum TG, total cholesterol, low-density-lipoprotein (LDL) cholesterol and high-density-lipoprotein (HDL) cholesterol were measured periodically in 116 breast cancer patients on adjuvant TAM therapy at a dose of 10 mg twice daily. The serum TG level was significantly increased 15 months after treatment, but the magnitude of increase was clinically insignificant in most patients (n = 102). If TG levels rose above 400 mg/dl, the dose of TAM was reduced to 10 mg once daily (n =14). The TG was lowered to a safer level after the dose reduction of TAM in 10 of 14 patients. The other four patients had early onset hypertriglyceridemia after beginning TAM (within 6 months), and their TG levels did not decrease satisfactorily after dose reduction. Hence, they required antilipemic medication with or without discontinuing TAM. This study suggests that reducing TAM from 10 mg twice daily to 10 mg once daily decreases the marked hypertriglyceridemia that occurs in some patients during TAM treatment.

Antineoplastic Agents, Hormonal↗
PubMed2000

Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL-lpr/lpr mice.

Previous study suggested that MRL-lpr/lpr mice treated with tamoxifen (TAM) had less severe proteinuria, reduced serum titre of anti-dsDNA autoantibodies and an increased survival rate. To investigate further the regulatory mechanisms of TAM on MRL-lpr/lpr female mice, a total dose of 200 microg per mice (5.5 mg/kg) was given every 2 weeks subcutaneously, while the control mice were injected with oil only. After being treated with TAM four times, the mice were killed and cellular functions were evaluated. The TAM-treated groups had smaller sized spleen and lymph nodes. Flow cytometric analysis of splenocytes had a significantly lower percentage of cell number of T cells and double negative T cells (CD4- CD8- T cells). There was no difference in cytokine production (interleukin (IL)-2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma)) from splenocytes stimulated with concanavalin A (Con A) or cytokines (IL-6) secreted by peritoneal exudate cells when stimulated with lipopolysaccharide (LPS). However, IL-2 from lymph node cells was significantly higher on TAM-treated mice. Finally, splenocytes or purified T cells stimulated with anti-CD3 antibody plus cross-linking immunoglobulin G (IgG) of the TAM-treated group had higher 3H-incorporation of proliferation assay compared with that of control groups. In vitro study further demonstrated that IL-2-activated proliferation of lymph node double negative (DN) T cells can be inhibited by TAM treatment in a dose-dependent manner. Our finding demonstrated that TAM may potentially influence T cells and modulate the immune function, which offers a novel approach to explore the feasibility of hormone therapy for autoimmune diseases.

Animals↗
PubMed2000

Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice.

It has been documented that sex hormone may play a role in the pathogenesis of murine lupus. To determine the effect of tamoxifen (TAM) on NZB/W F1 female mice, a total dose of 800 microg (22 mg/kg body weight) of TAM was administered subcutaneously every 2 weeks. The control mice were injected with peanut oil only. After treatment with TAM for 5 months, the mice were killed and immunological parameters were evaluated. The results suggest that NZB/W F1 mice treated with TAM had less severe proteinuria and increased survival rate compared to controls. Flow cytometric analysis of splenocytes revealed a significantly lower percentage of B cells and CD5+ B cells in the TAM-treated group. There was a significantly lower serum level of soluble tumour necrosis factor (TNF) receptor I and II molecules in the TAM-treated mice. Immunohistological study showed that control mice had severe immune complex deposition in the kidney. In contrast, TAM-treated mice had much less pathological change. In summary, this study demonstrated that TAM treatment might be able to alleviate the symptoms of lupus nephritis, influence B-cell count, modulate the expression of cytokine receptors and thereby subsequently affect immune function. Further studies to determine the cellular mechanisms in lupus nephritis may increase our understanding of this complex disease and provide additional targets for therapeutic intervention.

Animals↗
PubMedDate not supplied

Combined effects of tamoxifen and a chimeric humanized single chain antibody against the type I IGF receptor on breast tumor growth in vivo.

Proliferative and anti-apoptotic actions of IGFs are mediated by the IGF-I receptor (IGF-IR), to which both IGF-I and -II bind with high affinity. We previously reported that alphaIGF-IR scFv-Fc (scFv-Fc) consisting of the alphaIGF-IR scFv and human IgG (1) Fc domain retained general characteristics of the parental 1H7 monoclonal antibody, and significantly suppressed MCF-7 tumor growth. We proposed IGF-IR down-regulation as a possible mechanism for inhibition of MCF-7 tumor growth. To further determine the therapeutic potentials of this approach, in vivo effects of this antibody on breast tumor growth were evaluated in the absence or presence of tamoxifen (Tam) using a T61 human breast tumor model. T61 xenograft growth in athymic mice was compared under five conditions, PBS, scFv-Fc, Tam, scFv-Fc+Tam, and control antibody. While treatment with PBS and control antibody did not affect T61 tumor growth, scFv-Fc, Tam, and scFv-Fc+Tam treatments significantly suppressed the tumor growth during the first two weeks of treatment. Although the growth inhibitory effect of scFv-Fc during the first two weeks was significant, the tumor grew as rapidly as PBS-treated tumors thereafter. This rapid tumor growth was suppressed when scFv-Fc was combined with Tam. Throughout four weeks, the combined Tam+scFv-Fc treatment was more effective in inhibiting the T61 tumor growth than scFv-Fc or Tam treatment alone. scFv-Fc treatment down-regulated IGF-IR which appears to contribute to tumor growth inhibition. This study provides evidence that simultaneous targeting of IGF-IR and the estrogen receptor may enhance the therapeutic effect.

Animals↗
PubMed2002

Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression.

A prerequisite to the developement of an efficient cell and/or gene therapy for lung cancer is a precise characterization of the inflammatory cell populations spontaneously present in the tumor stroma associated with this cancer. This study was designed to define the cytotoxic potential and the relationship with stroma development of tumor infiltrating lymphocytes (TIL) and tumor associated macrophages (TAM). Tumor samples from 48 patients undergoing surgery for non-small cell lung cancer (NSCLC) were analyzed, by immunohistochemistry and in situ hybridization, with a panel of antibodies and probes specific for cell proteins linked to cytotoxicity, cytokines, and growth factors, and the replication status of TIL and TAM was evaluated by in vivo 5-bromodeoxyuridine incorporation. It was shown that, in NSCLC: (1) tumor stroma inflammatory cells are mainly TIL (approximately 2/3) (among them, 80 % are T-cells) and TAM (approximately 1/3), with almost no natural killer (NK) cells, and a few dentritic cells; (2) TAM and TIL are poorly replicating, but mainly recruited to the tumor stroma; (3) more than half TAM show an antibody-dependent cytotoxic potential, and one third of T-cells are TIA-1 positive CD8 activated cytotoxic lymphocytes; (4) cancer cells from only a few tumor express HLA class I and II antigens; (5) TAM production of cytotoxic cytokines [interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha)] and of transforming growth factor-beta1 (TGF-beta1) is low, in contrast to their strong release of platelet-derived growth factor (PDGF). We concluded that, in NSCLC, TIL cytotoxicity is likely to be low because of a poor class I MHC expression by tumor cells, and TAM low production of cytotoxic cytokines is a major limit to their possible cytotoxic activity. In contrast, TAM may favor tumor progression by contributing to tumor stroma formation and angiogenesis through their release of PDGF, in conjunction with TGF-beta1 production by tumor cells.

Biomarkers, Tumor↗
PubMed1991

Rapid induction of the c-jun protooncogene in the avian oviduct by the antiestrogen tamoxifen.

This report describes a rapid regulation of the expression of the c-jun protooncogene by the antiestrogen tamoxifen (Tam). The c-jun protooncogene codes for an important component of the AP-1 transcription factor complex, which regulates the expression of many unlinked genes. Repeated experiments have shown that Tam rapidly increases the steady-state c-jun mRNA levels in the avian oviduct but decreases the levels in the liver. The Tam effects are time- and dose-dependent. These results are supported by other studies that have demonstrated that 17 beta-estradiol decreases steady-state levels of c-jun protooncogene mRNA in oviducts of animals fully withdrawn from estradiol. The effect of Tam in the avian oviduct is in contrast to the reported effects of Tam on the expression of practically all other genes in the avian oviduct and other animal tissues. Transcription analyses using nuclear runoff experiments with oviduct nuclei demonstrate a decrease in the c-jun gene transcription within minutes after Tam treatment with a return to 75% of control values by 4 hr. The fact that Tam transiently decreases the transcription of the c-jun gene but increases the steady-state c-jun mRNA levels suggests that Tam must alter both transcriptional and post-transcriptional events. The results support a role of the c-jun protooncogene as a regulatory gene in the cascade model for steroid action whereby steroids rapidly regulate the regulatory genes, which in turn regulate many other structural genes.

Animals↗
PubMed1992

Tamoxifen advances puberty in the White Leghorn hen.

1. Tamoxifen (TAM) administration advances puberty in cockerels. In the present study the effect of TAM administration on the sexual development of White Leghorn hens was studied. 2. Two-week-old White Leghorn females were injected intramuscularly with TAM on alternate days at doses of 0.1 mg (0.1 TM), 1 mg (1TM), 5 mg (5TM) and 10 mg/kg body weight (10TM) respectively, while the controls were injected with maize oil (vehicle). The experiment was terminated at 23 weeks of age, when all the control hens laid eggs. Sample autopsies were made on chicks of 6, 14 and 23 weeks of age. 3. Body growth was not affected by any of the treatments. 4. Comb growth was accelerated by all doses of TAM, while hematocrit increased in the 1TM, 5TM and 10TM hens. 5. Egg laying advanced in the 0.1TM and 1TM birds, was delayed in 5TM hens and did not occur at all in the 10TM females. 6. TAM caused a precocious increase in plasma oestrogen and androgen, suppressed adiposity in a dose-related manner and, at low doses, advanced the development of the gonadal system. 7. At 23 weeks of age, when the gonadal system of the controls was fully active, TAM caused a dose-related depression in abdominal fat, liver, ovary, and oviduct weights, plasma total lipids and calcium concentrations and a dose-related increase in plasma oestrogen and androgen titres, and comb weight. 8. It seems that TAM increased gonadotropic activity and its androgen stimulating action, but suppressed peripheral signs of the elevated plasma oestrogen titres. Low doses of TAM enhanced gonadotropic activity and egg laying but the antioestrogenic effect depressed development of the gonadal system, suppressing egg production when high doses were administered. It therefore seems that oestrogens are necessary for normal ovarian development in hens.

Androgens↗
PubMed1993

Precocious puberty in tamoxifen-treated cockerels: hypothalamic gonadotrophin-releasing hormone-I and plasma luteinising hormone, prolactin, growth hormone and testosterone.

1. The administration of the anti-oestrogen, tamoxifen (TAM) to juvenile chicks results in precocious puberty. In the present study the effects of TAM administration (1 mg/kg body weight on alternate days from 12 d of age) on testicular function, hypothalamic chicken gonadotropin-releasing hormone (cGn-RH-I), plasma luteinising hormone (LH), growth hormone (GH), prolactin (PRL) and testosterone were studied in juvenile White Leghorn cockerels. 2. The increase in hypothalamic GnRH-I content which occurs during sexual development was advanced in TAM-treated birds, in association with precocious testicular development, an early rise of plasma testosterone content and enhanced comb growth. 3. Plasma LH concentrations behaved similarly and were higher in the TAM-treated than in control birds, during most of the experimental period. Plasma PRL concentration, which is high at hatching, decreased more quickly in TAM-treated than in control birds; plasma GH values were not consistently affected by TAM treatment. 4. Both the growth and the involution of the bursa of Fabricius in the TAM-treated cockerels preceded that in the control chicks. 5. It is concluded that TAM treatment induces precocious puberty in the cockerel by blocking the negative feedback action of aromatised testicular androgens on the hypothalamus.

Animals↗
PubMed2003

CYP2D6-mediated catalysis of tamoxifen aromatic hydroxylation with an NIH shift: similar hydroxylation mechanism in chicken, rat and human liver microsomes.

1. 4-Tritiated-tamoxifen (4-[(3)H]-tamoxifen) and 4-deuterated-tamoxifen (4-[(2)H]-tamoxifen) were synthesized to examine tamoxifen metabolism by human P450 (CYP) forms and also for the possibility of determining tamoxifen-4-hydroxylation in humans in vivo. 2. Liver microsomes from several species and cDNA-expressed human P450s were incubated with 4-[(3)H]-tamoxifen and the reaction monitored by assaying 4-hydroxytamoxifen (4-OH-tam) and (3)H(2)O formed. However, tamoxifen-4-hydroxylation did not generate stoichiometric amounts of (3)H(2)O and the expected unlabelled 4-OH-tam but instead yielded radiolabelled 4-OH-tam, apparently from [(3)H]-migration to the ortho-position, referred to as the NIH shift. 3. CYP2D6 was the prime catalyst of tam-4-hydroxylation, whereas CYP2B6, 2C9 and 2C19 yielded only low levels of 4-OH-tam; nevertheless, in all cases the 4-OH-tam was radioactive, apparently resulting from reactions involving an NIH shift. 4. Chicken liver microsomal preparation, being catalytically the most active in tamoxifen-4-hydroxylation, was incubated with deuterated tamoxifen (4-[(2)H]-tamoxifen) in order to determine whether an NIH shift occurs. Ion-trap mass-spectrometry of the HPLC-purified 4-OH-tam, from that incubation, indicated about 60% of [(2)H]-retention in 4-OH-tam, signifying an NIH shift. These findings indicate that the aromatic hydroxylation of tamoxifen does not entail hydroxyl insertion with an Sn2-displacement of hydrogen or a hydrogen isotope ((2)H or (3)H), but apparently involves epoxidation followed by migration of the (3)H, (2)H or (1)H to the ortho-position, and dissociation of the (1)H in preference to (3)H or (2)H, i.e. retention of the hydrogen isotope appears to be related to the bond strengths: C-(3)H>C-(2)H>C-(1)H.

Animals↗
PubMed1996

Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy.

Active cell death in hormone-dependent cells was studied using cultured human mammary carcinoma cells (MCF-7) treated with the anti-estrogens (AEs) tamoxifen (TAM), 4-hydroxy-tamoxifen (OH-TAM) or ICI 164 384 (10(-8)-10(-5) M) as a model. The following results were obtained. (i) In untreated MCF-7 cells a wave of replication occurred in the first 5 days of culture. All three AEs caused a dose-dependent inhibition of cell replication. (ii) TAM and OH-TAM at 10(-5) M, but not ICI 164 384, caused lytic cell death (necrosis) within 24 h, which was not inhibited by estradiol (10(-9)-10(-6)M). (iii) Lower concentrations of TAM or OH-TAM (up to 10(-6) M) or ICI 164 384 induced a more gradual appearance of cell death beginning at day 3. This type of cell death was inhibited by estradiol (10(-9) M), indicating its active nature. (iv) Nuclei showed two distinct patterns of alteration: (a) apoptosis-like condensation and fragmentation of chromatin to crescent masses abutting the nuclear envelope; (b) condensation of the chromatin to a single, pyknotic mass in the center of the nucleus, detached from the nuclear envelope. Quantitative histological evaluation revealed the predominance of pyknosis. (v) Biochemical DNA analysis revealed that only a relatively small amount of the total DNA was finally degraded into low molecular weight fragments (20 kb and less). (vi) Active cell death, with both apoptotic and pyknotic nuclear morphology, was associated with extensive formation of autophagic vacuoles (AV).3-Methyladenine, a known inhibitor of AV formation, partially prevented cell death as detected by nuclear changes. (vii) ICI 164 384 was about 10 times more effective than TAM or OH-TAM at inhibiting DNA synthesis, but had equal potency in inducing active cell death. It is concluded that AEs have anti-proliferative and anti-survival effects on MCF-7 human mammary cancer cells in culture. These two effects are under separate control because they differ by kinetics, dose dependence and sensitivity to the various AEs. Active cell death in MCF-7 cells seems to be initiated by autophagy, in contrast to concepts of apoptosis, and thus corresponds to autophagic/ lysosomal or type II death as previously defined. This may be important because of biochemical and molecular differences between these various subtypes of active cell death.

Autophagy↗
PubMed2004

Genotoxicity of tamoxifen citrate and 4-nitroquinoline-1-oxide in the wing spot test of Drosophila melanogaster.

Tamoxifen (TAM) is an anti-oestrogen used for treatment and prevention of human breast cancer, but it is also related to human endometrial and uterine cancer. The wing spot test in Drosophila melanogaster was employed to determine the genotoxic effects of TAM and 4-nitroquinoline-1-oxide (4-NQO), a carcinogen that produces adducts similar to TAM-DNA adducts detected in rodent liver and human liver microsomes. As Drosophila spp. have no oestrogen receptor, no effects can result in binding of TAM to a receptor. Chronic treatments with TAM citrate were performed with 3-day-old larvae of the standard (ST) and high bioactivation (HB) crosses of the wing spot test at concentrations of 0.66, 1.66 and 3.33 mM. In addition, the carcinogen 4-NQO was administered at 2.5 and 5.0 mM. Somatic spots on normal wings from marker-heterozygous flies and on serrate wings from balancer-heterozygous flies were scored to determine mutation and recombination events in somatic cells for each compound. The results showed genotoxic effects of TAM at 1.66 and 3.33 mM in the ST cross only and without a clear dose-response effect. This suggests a weak genotoxicity of this anti-oestrogen. The negative results obtained with TAM in the HB cross may indicate efficient detoxification of the compound by the increased xenobiotic metabolism present in this cross. As reported before, 4-NQO showed genotoxic effects in the ST cross with a clear dose-response effect. For the first time, we report enhanced effects of this compound in the HB cross. It is concluded that the genotoxicity of TAM in the Drosophila wing spot test is different from that of 4-NQO.

4-Nitroquinoline-1-oxide↗
PubMed1999

Pharmacokinetic interaction between etoposide and tamoxifen in patients with hepatocellular carcinoma.

The effect of tamoxifen (TAM) on the pharmacokinetics of oral administration of etoposide (VP-16) in patients with nonoperable hepatocellular carcinoma was investigated. The pharmacokinetics of VP-16 was studied by using a validated limited sampling strategy. The pharmacokinetic parameters of VP-16, such as area under curve (AUC), free AUC and protein binding, were determined from drug plasma concentrations at 1 and 4 h after VP-16 administration on the first day (day -1) and at the end of the chemotherapy cycle (day -21) for VP-16 alone and VP-16+TAM, respectively. When VP-16 was administered in association with TAM, the median total systemic exposure was not significantly (p = NS) different from that observed when VP-16 was administered alone [33.74 (range 11.19-56.58) versus 32.97 (range 20.23-119.28) mg/l/h]. Moreover, TAM did not affect significantly (p = NS) the levels of protein binding of VP-16 [median 94.6 (range 87.7-98.2) versus median 94.9 (range 91.6-98.0)% for VP-16+TAM and VP-16 alone, respectively] and the systemic exposure of the free drug (free AUC) [1.86 (range 0.21-4.57) versus median 1.78 (range 0.59-3.73) mg/l/h for VP-16+TAM and VP = 16 alone, respectively]. These results indicate a lack of pharmacokinetic interaction between VP-16 and TAM, and suggest that the increased hematological toxicity observed when TAM is given in combination with VP-16 could be related to pharmacodynamic interactions.

Aged↗