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PubMed2006

[Involvement of epidermal growth factor receptor signaling pathway in tamoxifen resistance of MCF-7 cells].

BACKGROUND & OBJECTIVE: Tamoxifen (TAM) is an important endocrine therapeutic drug used in combined treatment for breast cancer. However the drug resistant effect of TAM has become a major concern in clinical use. Epidermal growth factor receptor (EGFR) is expressed in many tumors and the expression of EGFR in breast cancer tissues is associated with poor prognosis. This study was to investigate EGFR signaling pathway in the drug resistant effect of TAM in breast cancer cells. METHODS: An estrogen receptor (ER) positive breast cancer cell line, MCF-7 was incubated with TAM (10(-7) mol/L) for up to 6 months to produce drug resistant cells. mRNA and protein expression of EGFR signaling pathway related genes and ER gene was analyzed by fluorescent quantitation reverse transcription-polymerase chain reaction (fqRT-PCR) and Western blot. AG1478, an EGFR inhibitor, was also used to study the drug resistant effect of TAM. RESULTS: The proliferation of MCF-7 cells was inhibited in the early stage after TAM treatment. However the inhibitory effect vanished after continuous 6-month treatment and the cell proliferation rate returned back to normal. The tolerance of MCF-7 cells to TAM was confirmed by cell growth inhibitory test. In TAM resistant MCF-7 cells, the expression of EGFR mRNA was increased by 4.5 times and the protein expression of EGFR, phosphorylation-extracellular signal-regulated kinase (p-ERK1/2) was also increased dramatically (P<0.05). While ER protein expression remained unchanged. Moreover the drug resistant cells were identified more sensitive to AG1478. CONCLUSION: In endocrine therapy, TAM resistant breast cancer cells are likely to be generated by the activation of EGFR signaling pathway after long-term TAM treatment, and EGFR inhibitors might increase the therapeutic effects in breast cancer treatment.

Antineoplastic Agents, Hormonal↗
PubMed1990

Chimeric calmodulin-cardiac troponin C proteins differentially activate calmodulin target enzymes.

To evaluate the role of domain I of calmodulin (CaM) in the activation of target enzymes, a series of CaM mutants was constructed in which domain I (49 amino acids) was substantially deleted, or was exchanged with the homologous region (58 amino acids) of cardiac troponin C (cTnC). The proteins are 1) aM, a mutant CaM in which domain I has been deleted; 2) TaM, first domain of cTnC, last three domains of CaM; 3) TaM-BMI, same as TaM, except the nonfunctional first Ca2(+)-binding domain has been restored by mutagenesis; 4) CaT, first domain of CaM, last three domains of cTnC. These proteins were evaluated for Ca2+ binding properties and as activators of three CaM target enzymes, CaM-dependent phosphodiesterase (PDE), smooth muscle myosin light chain kinase (MLCK), and CaM-dependent multifunctional protein kinase (CaM kinase II). The chimeric proteins containing four domains bound Ca2+ in the manner expected from the number and nature of EF hands. In contrast, aM bound only two Ca2+, suggesting that deletion of domain I may have disrupted binding in one of the remaining three domains, and did not activate the three enzymes. The kinetics of activation of PDE by CaM, TaM, and TaM-BMI were identical. Although cTnC and CaT could maximally activate PDE, the Kact for these mutants were greater than 2000 times than for CaM. All mutated proteins except CaT were poor activators of CaM kinase II and this protein activated the kinase to 65% that of CaM, with a nearly identical Kact. CaT and TaM, were poor agonists of MLCK. Activation of Ca2(+)-binding site I in TaM (TaM-BMI), completely prevented activation of MLCK. In addition, TaM-BMI was a potent competitive inhibitor of MLCK activation by CaM (Ki = 66 nM). We conclude 1) a domain I is necessary to activate these target enzymes, and the substitution of the corresponding region of cTnC into CaM leads to differential effects; 2) an active first Ca2(+)-binding site is not essential for activation of PDE and the primary sequence of the first domain of CaM need not be highly conserved; 3) for CaM kinase II, determinants in the first domain are critical whereas more flexibility exists for the remaining three domains; 4) since TaM-BMI acts as a potent competitive inhibitor of MLCK binding of CaM to a target enzyme and activation can be dissociable events.

Amino Acid Sequence↗
PubMed1990

Expression of c-fos proto-oncogene in tumor-associated macrophages.

Tumor-associated macrophages (TAM) have peculiar membrane phenotype and functional properties. In an effort to unravel possible molecular determinants associated with the reprogramming of mononuclear phagocytes that infiltrate tumors, we have investigated the expression of immediate-early genes in TAM from murine sarcomas. c-fos is a prototypic immediate oncogene, with transregulatory function on gene transcription, expressed by myelomonocytic cells and induced by certain activation signals. TAM from three murine sarcomas expressed basal levels of c-fos transcripts considerably higher than those of peritoneal exudate macrophages (PEM). Activation of myelomonocytic cells by bacterial LPS is associated with an early transient increase in c-fos transcription. Unlike PEM, TAM did not show any increase in c-fos expression after exposure to LPS. A similar unresponsiveness to LPS stimulation was observed in macrophages isolated from peritoneal ascitic tumors. c-fos expression in macrophages can be induced via protein kinase C activation or via an increase in cAMP levels. Unlike PEM, TAM did not respond to the protein kinase C activator PMA and to cholera toxin. After culture for 18 to 20 h, c-fos expression in TAM declined, and concomitantly, TAM completely recovered responsiveness to LPS in terms of augmented oncogene mRNA levels. These results demonstrate that TAM from murine sarcomas have an altered expression of the c-fos proto-oncogene, with high basal levels and unresponsiveness to augmenting signals, reversible upon in vitro culture. The altered c-fos expression in TAM may reflect exposure to cytokines present in the tumor microenvironment and may underlie at least some of the peculiar properties of TAM.

Animals↗
PubMed1989

Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens.

This investigation examines the tamoxifen (TAM)-dependent growth in vivo of an MCF-7 tumor variant, MCF-7TAM, previously reported in this journal (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988). Ovariectomized athymic mice were implanted with 1-mm3 pieces of MCF-7TAM and were treated with Silastic capsules of varying sizes containing TAM to demonstrate dose-dependent growth over a 10-wk experiment. TAM was necessary to maintain tumor growth. Animals whose capsules were removed at 6 wk showed complete tumor stasis after 20 wk of observation. Removal of TAM after 11 wk caused the rate of tumor growth to decrease compared with TAM-treated animals. Tumor areas were significantly different (P less than 0.03) at Wk 20. The growth of TAM-stimulated tumor, MCF-7TAM, was inhibited by the novel steroidal antiestrogens, ICI 164,384 and RU 39,411. TAM-stimulated growth (0.5-cm Silastic capsule) was maintained at control levels by 8 wk of treatment with ICI 164,384 (1 mg s.c. every other day). ICI 164,384 alone had no stimulatory activity. At the same dose, RU 39,411 inhibited TAM-stimulated growth of MCF-7TAM, although not to control levels. RU 39,411 was slightly stimulatory when administered alone. The growth of MCF-7TAM was stimulated by either TAM or 17 beta-estradiol. The antiestrogen, RU 39,411, effectively inhibited estradiol-stimulated tumor growth. Overall, these studies confirm and extend the previous observation on TAM-stimulated growth of breast cancer cells in vivo and demonstrate the possibility of developing novel antiestrogens to prevent this form of drug resistance should it occur in the clinic.

Animals↗
PubMed1987

Experimental endocrinotherapy with tamoxifen of human ovarian dysgerminoma transplanted into nude mice.

The effect of Tamoxifen (TAM) on tumor growth was investigated experimentally using ovarian dysgerminoma serially transplanted into nude mice. The mice were divided into two groups according to estrogen receptor (ER) content of initially transplanted tumor; groups TAM-A and -B indicated ER rich and ER poor tumor, respectively. Their own control (CNT) was included in each group. After TAM treatment, the tumor size of TAM-A and -B groups was 150 fold and 350 fold that of initial tumor respectively, while that of group CNT was over 500 fold, suggesting that a strong anti-tumor effect of TAM was exerted especially on ER rich tumor. Histological changes following tamoxifen treatment such as a decline in the size of tumor cells and nuclei as well, and a decrease in the mitotic index were observed only in the TAM-A group. The concentration of ER and progesterone receptor (PR) in the cytosol of these tumors were measured. The ER levels in the initial tumor tissue of TAM-A and -B were 14.7 and 3.3 fmol/mg protein, respectively. The significant increase in PR content in TAM-A following TAM administration obviously indicated a so-called TAM-dependent PR induction effect. These results indicated that ovarian cancer containing ER, even though it originated from germ cells, would be responsible for antiestrogen therapy.

Animals↗
PubMed1986

Ia antigen expression and IL-1 activity in murine tumour-associated macrophages.

Tumour-associated macrophages (TAM) isolated from five murine sarcomas had a relatively high frequency of I-A+ cells, with mean values of 27% (mFS6), 52% (MN/MCA1), 68% (N3), 62% (N4) and 98% (J3) for TAM compared to 12% for resident peritoneal macrophages. Expression of I-E in TAM was also high (29%) in the only sarcoma (N4) examined in this respect. Expression of I-A by TAM declined in culture but exposure to lymphokine supernatants maintained and increased the frequency of I-A+ cells in TAM. Transplantation of tumours into nude mice caused a marked decrease in the percentage of I-A+ TAM in the case of the N4 sarcoma (8% compared to 48%), whereas for the MN/MCA1 sarcoma the diminution was only marginal (from 53 to 41%), TAM from murine sarcomas did not constitutively release appreciable levels of interleukin-1 (IL-1) activity. Upon stimulation with bacterial lipopolysaccharides or silica, TAM showed a limited capacity to produce and release IL-1 activity compared to peritoneal macrophages. Thus the expression of I-A antigens and the IL-1-producing capacity are uncoupled in TAM from murine sarcomas. These properties of TAM could play an important role in the generation of anti-tumour immunity and/or of suppressive T-cell circuits.

Animals↗
PubMed1986

Tumor associated macrophage mediated lysis of autologous tumor cells.

Lysis of autologous tumor cells (ATC) mediated by the tumor associated macrophages (TAM) was studied by 4 h 51Cr-release assay at different days of growth of a transplantable ascites tumor, S-180, inoculated in adult male Swiss mice. The ATC were coated with serum of tumor bearing mice. On day 3 after tumor inoculation the TAM mediated a remarkable lysis of the tumor serum coated ATC. With advancement of tumor growth the cytolysis by TAM decreased gradually to the basal level at day 10 and totally abrogated at day 12. Also the binding of the tumor serum coated ATC by TAM varied at different days of tumor growth. At early phases of tumor growth high lytic activity of the TAM was correlated with augmented target binding. The observed lysis may be considered as antibody dependent cell mediated cytotoxicity (ADCC) extended by the TAM, since presence of specific tumor antibodies were demonstrated in the tumor serum used for coating ATC. No significant lysis was recorded when the ATC was coated with normal serum or used as such for direct lysis by the TAM. In vitro treatment of the TAM with suitable doses of Levamisole and Polyionosinic-polycyticyclic acid further augmented the TAM mediated high level of ADCC at day 3 with no change in its binding of ATC. The immunopotentiators enhanced both ADCC and target binding ability of the functionally depressed TAM at day 10.

Animals↗
PubMed1987

Macrophage content of murine sarcomas and carcinomas: associations with tumor growth parameters and tumor radiocurability.

Experiments were designed to investigate whether the tumor-associated macrophage (TAM) content of murine solid tumors correlates with the clonogenic ability of tumor cells to establish s.c. tumors, tumor growth rate, extent of tumor necrosis, tumor metastatic propensity, and tumor radioresponse. Of 13 tumors studied, 6 were sarcomas and 7 were carcinomas; all tumors were of spontaneous origin in C3Hf/Kam mice, with the exception of one sarcoma that was induced by 3-methylcholanthrene. Tumors were growing in the hind thighs of syngeneic mice, and their TAM content was determined when they were 8 mm in diameter. The TAM content varied greatly among tumors, ranging from 9 to 83%. Tumor bearing mice experienced a reduction of 50% or more in the number of peritoneal macrophages, but the degree of reduction was independent of TAM content. A significant negative correlation was noted between TAM content and TD50 values (i.e., the number of tumor cells needed to produce tumors in 50% of injected sites) and between TAM content and the amount of tumor necrosis. Also, an obvious trend toward positive correlation between TAM content and reduced local tumor radiocurability was apparent. No correlation was found between TAM content and tumor growth rate or metastatic spread. TAM from the NFSA sarcoma (a tumor with a low TD50 value, almost without necrosis, and poorly responsive to radiation) stimulated the in vitro growth of NFSA tumor cells. These observations suggest that high TAM content could be conductive to tumor cell proliferation and could be a factor in poor tumor radioresponse.

Animals↗
PubMed1984

Induction of two estrogen-responsive proteins by antiestrogens in R27, a tamoxifen-resistant clone of MCF7 cells.

In an attempt to approach the mechanism by which estrogen and antiestrogen regulate the growth of estrogen receptor-positive breast cancer, we have studied the effects of the antiestrogens tamoxifen (TAM) and 4-hydroxytamoxifen (OH-TAM) on the induction of two estrogen-specific proteins in a variant of MCF7 cells termed R27, cloned for its ability to grow in the presence of TAM. We found that, in the R27 variant, antiestrogens as well as estradiol were able to increase specifically the production of a Mr 52,000 protein which was released into the culture medium. This protein was shown to be identical to the Mr 52,000 glyco-protein induced by estrogen and released by MCF7 cells on the basis of its specific inducibility by physiological concentrations of 17 beta-estradiol and of its resolution in two-dimensional gel analysis. Dose-response analysis showed that, in the R27 variant, TAM and OH-TAM acquired the ability to induce the Mr 52,000 protein at concentrations compatible with their relative affinities for the estrogen receptor, while these antiestrogens were inefficient in the wild MCF7 cells. Whereas the relative increase of the Mr 52,000 protein was similar with TAM, OH-TAM, and 17 beta-estradiol, the general production of Mr 52,000 and of total labeled proteins was less with the antiestrogens than with 17 beta-estradiol. Moreover, OH-TAM displayed a biphasic dose-response curve with inhibitory effects at concentrations above 10 nM, suggesting an additional mechanism. Neither TAM nor OH-TAM had any antiestrogenic effect when added in the presence of 17 beta-estradiol. In the R27 variant, both estradiol and antiestrogens induced the progesterone receptor sites; however, the extent of the stimulation was lower with antiestrogens than with estradiol. This study shows that, in addition to the classical antiestrogen-resistant breast cancer cells, in which the estrogen receptor is absent or inactive, there is another class of antiestrogen-resistant cells in which the drug becomes a full estrogen agonist as evidenced by the induction of the Mr 52,000 estrogen-specific protein, which is not induced in the wild-type cells.

Breast Neoplasms↗
PubMed1993

[Clinical evaluation of NK 622 (toremifene citrate) in advanced or recurrent breast cancer--a comparative study by a double blind method with tamoxifen].

Efficacy and safety of NK 622 (toremifene citrate) were compared with tamoxifen (TAM) by a double blind test in patients with advanced or recurrent breast cancer. NK 622 and TAM were given orally for 12 weeks or more at daily doses of 40 and 20 mg/body, respectively. Eligible cases in NK622 and TAM groups were both 57 patients. No significant difference was observed in patient characteristics between either group. Response rates were 26.3% (8 CR and 7 PR, 15/57) in the NK 622 group and 28.1% (3 CR and 13 PR, 16/57) in the TAM group. Median values of duration to onset of CR were 91 days in the NK 622 group and 169 days in the TAM group. The duration was significantly shorter with the NK 622 group. Median duration of efficacy in CR and PR cases was 155 days in the NK 622 group and 154.5 days in the TAM group. Adverse effects were encountered in 7 patients (12.3%) of each of the 2 groups. The side effects were fatigue, hot flush, WBC decrease, abnormal values in liver function tests, etc. in the NK 622 group and anorexia, nausea, eruption, feeling of warmth, sweating, dry mouth, dizziness, abnormal values in liver function tests, etc. in the TAM group. Administration was discontinued in one patient with eruption and another patient with abnormal values of liver function tests in the TAM group, while there was no such case in the NK 622 group. Including the discontinued cases, the side effects were moderate and reversible in both groups. The patients in whom a drug was determined as useful or more numbered 24/57 (42.1%) in the NK 622 group and 23/57 (40.4%) in the TAM group. There was not significant difference between the 2 groups in the above results except the duration to onset of CR. From these results, NK 622 is expected to show comparable efficacy, safety, and usefulness in patients undergoing TAM treatment for advanced or recurrent breast cancer.

Administration, Oral↗
PubMed1996

Evidence that the catechol 3,4-Dihydroxytamoxifen is a proximate intermediate to the reactive species binding covalently to proteins.

Metabolism of tamoxifen by rat and human hepatic microsomal cytochrome P450s (CYPs) forms a reactive intermediate that irreversibly binds to microsomal proteins (C. Mani and D. Kupfer, Cancer Res., 51: 6052-6058, 1991.). The current study examines the nature of the tamoxifen metabolite that is proximate to the reactive intermediate(s). The rate of covalent binding of tamoxifen metabolites, tamoxifen N-oxide, N-desmethyltamoxifen, and tamoxifen N-oxide-epoxide was approximately equal to or less than that of tamoxifen. By contrast, covalent binding of 4-hydroxytamoxifen (4-OH-tam) was 3-5-fold higher than that of tamoxifen, indicating that among the metabolites examined, 4-OH-tam or its metabolite(s) is most proximate to the reactive intermediate(s). Incubation of 4-OH-tam with liver microsomes from PCN-treated rat yielded three detectable metabolites. One was identified as 4-OH-tam N-oxide via its facile reduction back to 4-OH-tam by titanium(III) chloride. Another metabolite of 4-OH-tam, assumed to be 3,4-dihydroxytamoxifen (3,4-di-OH-tam) catechol, was demonstrated by its monomethylation with [3H]S-adenosyl-L-methionine ([3H]SAM) in presence of endogenous catechol-O-methyltransferase. Monomethylated catechol from 4-OH-tam was formed at a 3-4-fold higher rate than from tamoxifen. It was reasoned that if the catechol is most proximate metabolite to the reactive intermediate, then its methylation would reduce the formation of the reactive intermediate and result in lower rate of covalent binding. In fact, addition of radioinert SAM to incubations of tamoxifen inhibited covalent binding by 17-23%. By contrast, inclusion of 1.0 mM S-adenosyl-L-homocysteine, a potent inhibitor of catechol-O-methyltransferase-mediated methylation of 3,4-di-OH-tam, essentially overcame the inhibition of the covalent binding by SAM. Additionally, ascorbic acid and glutathione, inhibitors of covalent binding of tamoxifen, produced an elevation of methylated catechol. These findings collectively indicate that 3,4-di-OH-tam is proximate to the ultimate reactive intermediate that results in covalent binding to microsomal proteins.

Animals↗
PubMed1997

Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus.

To assess the effects of chronic administration of tamoxifen (TAM) and toremifene (TOR) on genetic damage related to carcinogenesis, we measured DNA adduct formation by (32)P-postlabeling in liver, kidney, and uterus of Fischer rats given TAM or TOR in the diet for 18 months. TAM induced high levels of DNA adducts in the liver in a dose-dependent manner. The total adduct levels were 3000 +/- 870 and 6100 +/- 1500 adducts per 10(9) nucleotides for the 250- and 500-ppm groups, respectively. TOR induced a dose-dependent level of adducts that was lower than that observed for TAM. The total hepatic adduct level was 70 +/- 5, 130 +/- 20, and 70 +/- 20 for 250, 500, and 750 ppm TOR, respectively. Both TAM and TOR induced a low level of adducts in the kidney, and TOR significantly enhanced endogenous DNA adduct formation. The total adduct level was 480 +/- 140, 420 +/- 210, and 680 +/- 80 adducts per 10(9) nucleotides for control, 500 ppm TAM, and 500 ppm TOR, respectively. Although neither TAM nor TOR induced adducts in the uterus, TAM significantly enhanced endogenous DNA modifications in this tissue. The total uterine adduct level was 70 +/- 30, 130 +/- 50, and 70 +/- 20 for control, 500 ppm TAM, and 500 ppm TOR, respectively. These observations demonstrate a correlation between DNA adduct formation and carcinogenicity for these compounds. The effectiveness of TOR and TAM in increasing endogenous DNA adducts indicates that a mechanism other than direct DNA damage may also be involved in their carcinogenicity.

Animals↗
PubMed1998

Anti-estrogens induce apoptosis of multiple myeloma cells.

Previous studies have suggested that multiple myeloma (MM) cells express estrogen receptors (ER). In the present study, we characterized the effects of estrogen agonists and antagonists (anti-estrogens [AE]) on growth of MM cell lines and MM patient cells. In addition to antagonizing estrogen binding to ER, AE can trigger apoptosis. Hence, we also determined whether estrogens or AE altered MM cell survival. Immunoblotting showed that ER-alpha is expressed in 4 of 5 MM cell lines (ARH-77, RPMI 8226, S6B45, and U266, but not OCI-My-5 cells), as well as in freshly isolated MM cells from 3 of 3 patients. 17beta-estradiol (E2) did not significantly alter proliferation of MM cell lines or MM patient cells. In contrast, two structurally distinct AE, tamoxifen (TAM) and ICI 182,780 (ICI), significantly inhibited the proliferation of all 5 MM cell lines and MM cells from 2 of 2 patients (IC50, 2 to 4 micromol/L). Proliferation of these cell lines was also inhibited by the hydroxylated TAM derivative, 4-hydroxytamoxifen (4HTAM), although this derivative was less potent than TAM (IC50, 3 to 25 micromol/L). In contrast, the dehalogenated TAM derivative toremifene (TOR) did not inhibit MM cell proliferation. We next examined the effects of these agents on MM cell survival. TAM, ICI, and, to a lesser extent, 4HTAM and TOR triggered apoptosis in both ER-alpha-positive as well as ER-alpha-negative MM cell lines and patient MM cells, evidenced both by fluorescence-activated cell sorting (FACS) analysis using propidium iodide staining and the TUNEL assay. TAM-induced growth inhibition and apoptosis of ER-alpha-positive S6B45 MM cells was not blocked by coculture with excess E2. TAM-induced apoptosis of S6B45 MM cells was also unaffected by addition of exogenous interleukin-6. Importantly, both the inhibition of MM cell proliferation and the induction of MM cell apoptosis were achieved at concentrations of TAM (0.5 and 5.0 micromol/L) that did not significantly alter in vitro growth of normal hematopoietic progenitor cells. Similar plasma levels of TAM have been achieved using high-dose oral TAM therapy, with an acceptable toxicity profile. These studies therefore provide the rationale for trials to define the utility of AE therapy in MM.

Apoptosis↗
PubMed1986

Oral high-dose medroxyprogesterone acetate versus tamoxifen. A randomized crossover trial in postmenopausal patients with advanced breast cancer.

In a prospective randomized multicenter study in previously untreated postmenopausal patients with advanced breast cancer, the response to treatment with oral medroxyprogesterone acetate (MPA) 300 mg three times daily was compared with tamoxifen (TAM) 20 mg twice daily. Of 61 patients treated with MPA, 27 (44%) had a partial or complete remission, 6 showed no change, and 28 had progressive disease. Of 68 patients treated with TAM, 24 (35%) showed a remission, 15 no change, and 29 progression. The difference in response rate is not significant. However, 11 of 25 patients with osseous metastases as predominant site, responded to MPA and 7 of 31 to TAM (P = 0.05). Moreover, in patients older than age 70 years, 13 of 26 responded to MPA and 6 of 31 to TAM (P less than 0.05). Median duration of remission of all patients in the MPA arm was 17 months and in the TAM arm, 23 months (not significant). Median survival was 20 months for MPA and 26 months for TAM (not significant). After cross-over from TAM to MPA 8 of 31 patients responded and after cross-over from MPA to TAM, no response was seen in 27 patients. These data indicate that the response rate and duration to MPA and TAM are comparable, except in patients with osseous metastases and in patients older than age 70 years. MPA has more side effects, but seems to be more effective after cross-over, and may thus be reserved for second-line treatment.

Aged↗
PubMed1987

Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen versus nandrolone decanoate.

The response to tamoxifen (TAM) (10 mg to 20 mg twice orally) was compared with the response to nandrolone decanoate (NAN) (50 mg every second week or 100 mg every third week intramuscularly) in this randomized study in previously untreated women with advanced breast cancer. Patients were postmenopausal or postmenopause was induced with irradiation therapy. The two treatment groups were highly similar in different patient characteristics. Of 67 evaluable patients treated with TAM, ten (15%) had a complete or partial remission, 28 (42%) had stabilized disease and 29 (43%) had progressive disease. In the 60 patients treated with NAN, the figures were ten (17%), 22 (37%) and 28 (47%) respectively. The response rates did not differ significantly. Tam was as good as NAN in osseous metastases. Four of 34 patients responded to TAM and three of 38 patients responded to NAN. NAN had a tendency for better response in the treatment of visceral metastases. Six (43%) of 14 patients responded to NAN while only three (14%) of 21 responded to TAM (P = 0.11). The median duration of remission was 24 months in the TAM arm and 17 months in NAN (insignificant). As second line treatment, NAN after TAM gave one complete remission and three partial remissions, but none responded to TAM after NAN. The side-effects of both drugs were rare and mild. These data indicate that TAM and NAN are comparable in the treatment of advanced breast cancer.

Breast Neoplasms↗
PubMed1993

Tamoxifen modulation of cisplatin resistance in patients with metastatic melanoma. A biologically important observation.

BACKGROUND: Treatment with the four-drug combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and tamoxifen (TAM) has resulted in an overall response rate of more than 50% in patients with metastatic melanoma. Deletion of TAM from the regimen resulted in a decrease in the response rate to 10%, suggesting an important role for TAM. The authors have subsequently demonstrated that TAM is highly synergistic with DDP in a human melanoma cell line, T-289, which supports the clinical observation that TAM is important in this regimen. The authors conducted a clinical trial to determine whether the addition of TAM can overcome established DDP resistance in patients with malignant melanoma. METHODS: Patients with metastatic melanoma were initially treated with DDP 100 mg/m2 alone until they demonstrated DDP resistance. On the next cycle of treatment, patients received TAM 40 mg by mouth four times a day on the day before DDP treatment followed by 20 mg by mouth daily for the rest of the 3-week cycle plus the same dose of DDP. RESULTS: Among 24 patients treated with DDP alone there were one complete and two partial responses. Twenty patients, in whom single-agent DDP failed, were treated with the combination of TAM and DDP. Of these 20 patients, 19 were evaluable for response. Among these 19 patients, there were three partial responses (16%) and three mixed responses (16%), for an overall response rate of 32% (0% was expected) (P < 0.001). If the three mixed responses are eliminated, the statistical significance is of borderline significance (P = 0.058). CONCLUSIONS: The addition of TAM to DDP can overcome established DDP resistance in a subset of patients with metastatic melanoma.

Adult↗
PubMed2000

Current and future directions in medical therapy for breast carcinoma: endocrine treatment.

Endocrine therapy remains a mainstay of treatment for breast carcinoma in both adjuvant and metastatic settings. The choice of endocrine therapy is guided by the presence and degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) as well as by clinical parameters. Adjuvant tamoxifen (TAM) given for 5 years is accepted standard therapy for postmenopausal ER and/or PgR positive (+ve) women. In premenopausal women, 5 years of TAM given alone has similar effects, but is used less frequently because chemotherapy has been regarded as a standard even in ER and PgR +ve women. Recent literature has demonstrated the equivalence or superiority of (Zoladex [ZOL], Zeneca Pharmaceuticals, Wilmington, DE) goserelin acetate plus TAM to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy in premenopausal ER and PgR +ve women. This, together with older data showing equivalence or superiority of ovarian ablation (OA) to CMF chemotherapy in the same setting, as well as accumulating data suggesting benefit from the addition of ZOL, OA, and/or TAM to chemotherapy in the premenopausal adjuvant setting, has raised issues regarding whether ZOL, OA, and/or TAM can substitute for chemotherapy or should always be added to it for premenopausal receptor +ve women. In the metastatic setting, the second-generation aromatase inhibitors (AI) clearly have moved into position as second-line therapy after TAM. Recent data have shown equivalence and perhaps some superiority to TAM by at least one AI (anastrazole [AN]) in first-line metastatic treatment. The results of adjuvant studies comparing TAM, AN, and TAM + AN in the adjuvant setting will be awaited with great interest. In the interim, the development of other SERMS (raloxifene, EM 850) and of pure antiestrogens may provide new and exciting approaches in the metastatic, adjuvant, and preventive settings.

Breast Neoplasms↗
PubMed2002

The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies.

The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour-associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti-tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour-derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro-environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro- and anti-tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours.

Cell Count↗