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Biomedical subjects

L Kangas

Publications and source records attributed to L Kangas.

At least 55 records · Page 3Linked to original sources
PubMed1991

Determination of 2-fluoro-2-deoxy-D-glucose uptake and ATP level for evaluating drug effects in neoplastic cells.

The glucose analogue 2-fluoro-2-deoxy-D-glucose (FDG) was used to study chemosensitivity of two human ovarian cancer cell lines and of murine L1210 cells. Cell viability was determined by measuring intracellular adenosine triphosphate (ATP) with a bioluminescence method, which has been shown to correlate closely with trypan blue, stem cell, and [3H]TdR assays. All three cell lines were sensitive to cytostatic drugs, which exerted a parallel decrease in the intracellular FDG and ATP levels. The two measures correlated positively (r = 0.66, P less than 0.001), indicating that FDG uptake is closely linked with ATP production. Relatively low hexokinase (HK)-to-glucose 6-phosphatase (HK/G6-Pase) ratios were measured, which suggests that the metabolic trapping of FDG 6-phosphate within the cytosol is incomplete. Apparently, these cell lines may not depend exclusively on glycolysis for their energy requirement. We conclude that cell killing caused by cytostatic drugs is associated with a decreased ATP content and FDG uptake. This indicates that not only ATP but also FDG may be used to study drug effects in vitro.

Adenosine Triphosphate↗
PubMed1990

Review of the pharmacological properties of toremifene.

New compounds were synthesized with the aim to develop new anti-estrogenic antitumor drugs. The biological properties of the molecules were screened by (1) estrogen receptor (ER) binding, (2) effect on MCF-7 cells, (3) uterotrophic effect and inhibition of estradiol induced uterotropic effect and (4) antitumor effect in DMBA induced rat mammary cancer. One of the molecules, Fc-1157a = toremifene, exhibited the following characteristics: competitive inhibition of [3H]estradiol binding to ER (IC50 = 0.3 mumol/l), inhibition of MCF-7 cell growth in a concentration-dependent manner and cell-killing effect at higher than 3 mumol/l concentrations. Minimal estrogenic dose of toremifene on rat uterus weight was about 40 times higher than that of tamoxifen. Toremifene had statistically significant effect against DMBA-induced rat mammary cancer. Further screening consisted of antitumor, pharmacokinetic and safety studies. Toremifene inhibited the growth of ER-negative, glucocorticoid sensitive, mouse uterine sarcoma in a dose-dependent manner. Pharmacokinetics and metabolism of toremifene resembled closely those of tamoxifen, but since the chlorine atom of the toremifene molecule was not metabolically cleaved tamoxifen and toremifene did not have chemically similar metabolites. Toremifene was well tolerated in animal toxicity studies. No hyperplastic or neoplastic nodules, which were seen in almost all high-dose (48 mg/kg for 24 weeks) tamoxifen-treated rats, were found in toremifene-treated rats (dose 48 mg/kg). In clinical phase I studies in healthy voluntary postmenopausal women, no side effects were reported, at doses less than or equal to 460 mg, neither after a single dose nor after five daily doses. At the dose of 680 mg two out of five persons experienced vertigo and headache. Toremifene, at the dose of 68 mg daily, had antiestrogenic effect on estradiol-induced human vaginal epithelial cells. Clinical phase II studies have confirmed that toremifene has a promising antitumor effect.

Animals↗
PubMed1990

Effect of toremifene on the activity of NK-cells in NZB/NZW mice.

The effect of toremifene on NK-cells isolated from the spleen of NZB/NZW mice was studied in comparison to tamoxifen and estradiol. Unlike estradiol but like tamoxifen, toremifene did not influence the activity of NK-cells. Low doses (0.1 and 10.0 mg/kg) of toremifene did not suppress, but a high dose of toremifene and tamoxifen (50 mg/kg for 6 weeks) suppressed the stimulating effect of human interferon alpha on the cells.

Animals↗
PubMed1990

Metabolism of toremifene in the rat.

Toremifene was labelled to a specific activity of about 20 microCi/mmol with tritium at positions 3 and 5 in the para-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways. A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 microCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and N-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.

Administration, Oral↗
PubMed1990

Effect of toremifene on estrogen primed vaginal mucosa in postmenopausal women.

The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied in postmenopausal women volunteers primed for 7 days with estradiol valerate (2 mg daily orally) which was continued throughout the study. A control group received estrogen only and a reference group estrogen with 60 mg tamoxifen for 5 days. No treatment opposed the action of the estrogen on the endometrium but both 68 mg toremifene and 60 mg tamoxifen statistically significantly decreased the maturity index of vaginal cells on day 13. A decrease was also evident on day 18 with 20 mg toremifene.

Biopsy↗
PubMed1990

Hormonal effects of toremifene in breast cancer patients.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.

Adult↗
PubMed1990

Antitumor effects of combination toremifene and medroxyprogesterone acetate (MPA) in vitro and in vivo.

The estrogen (ER) and progesterone (PgR) receptor levels in various gynecological tumors were measured. The same tumors were exposed in vitro to toremifene, MPA or their combination and the growth of the tumors was followed by measuring the adenosine triphosphate (ATP) within the cells by a simple bioluminescence assay. Altogether 34 clinical samples were studied. DMBA-induced mammary tumors bearing rats were treated in vivo with toremifene, MPA and their combination. About half of the ovarian cancers and 6 out of the 7 adenocarcinomas of uteri contained ER. The ovarian tumors were PgR rich in 25% and adenocarcinomas of uteri in 6 out of the 7 cases. When compared to control toremifene (concentration 1 mumol/l) was able to decrease the number of living cells to 50% or less in 9/34 samples, MPA (concentration 10 mumol/l) in 17/34 samples, and the combination in 25/34 samples. In five cases the antitumor effect of the combination was synergistic. In two cases signs of weak antagonism were seen. In vivo the antitumor effect of toremifene and MPA was clearly synergistic against DMBA-induced cancers. The effect was dose-dependent and at sufficiently high doses it was possible to eradicate the tumors and cure the animals.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Additive and synergistic antitumor effects with toremifene and interferons.

MFC-7 cells were exposed to toremifene, human alpha and gamma interferons and combinations of them in vitro. Growth of the cells was followed by ATP bioluminescence method. Rats bearing DMBA-induced tumors were treated with toremifene, rat gamma interferon and their combination daily for five weeks. The growth of the tumors was followed by palpation weekly. Toremifene and interferons inhibited the growth of MCF-7 cells. Interferons alpha and gamma were additive; toremifene and interferons were additive or at the best synergistic. Toremifene inhibited the growth of DMBA-induced tumors. Rat gamma interferon alone had no clear effect on the tumor growth. Combination of toremifene and gamma interferone was the most effective treatment and did not show any detectable toxicity. Toremifene and interferons have interesting interactions. Clinical studies using the combination might be warranted.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Biochemical and pharmacological effects of toremifene metabolites.

Toremifene, a new antiestrogenic antitumor compound, has several biologically active metabolites. The hormonal effects of the main metabolites resemble those of unchanged toremifene. The main metabolite in humans, N-demethyltoremifene, is bound to estrogen receptors (ER), inhibits the growth of MCF-7 cells, and exerts an antiestrogenic effect similar to that of toremifene. However, its antitumor effect in vivo against dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancers is weaker than that of toremifene. Didemethyltoremifene has antiestrogenic actions in mouse and rat uterus at high doses. 4-Hydroxytoremifene is bound to ER with higher affinity and inhibits MCF-7 growth at concentrations lower than those of toremifene. It has a weaker intrinsic estrogenic effect than does toremifene. The efficacy of 4-hydroxytoremifene against DMBA-induced cancers is weak except at very high doses. Oxidations of N-demethylated metabolites to (deamino)hydroxylated compounds and carboxylic acids are the detoxification routes of toremifene. (deaminohydroxy)Toremifene has only weak hormonal actions at high doses and carboxylated metabolites have no estrogenic/antiestrogenic effects. The antitumor effect of toremifene in vivo is mainly due to unchanged toremifene, but hormonal effects (which may have a role in antitumor actions) are partly attributable to metabolites N-demethyltoremifene, didemethyltoremifene, (deaminohydroxy)toremifene, 4-hydroxy-N-demethyltoremifene, and 4-hydroxytoremifene, which have pharmacological properties similar to those of toremifene.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Introduction to toremifene.

Toremifene, a triphenylethylene antiestrogen first synthesized in 1981, binds to the estrogen receptor with an affinity about 5% that of estradiol. Its antiestrogenicity/estrogenicity ratio in animal models is about 5 times that of tamoxifen, though it requires somewhat higher doses for full effectiveness, and it is active against breast cancer in animal and cell culture models. It has a long elimination half-life and there are several metabolites, but the principal antitumor activity appears to be due to the unchanged drug. In Phase I and Phase II clinical trials, toremifene has shown good response rates in ER-positive or ER-unknown tumors, and significant responses after failure of tamoxifen or other hormonal or chemotherapeutic regimens, with rare and mild side effects.

Adenocarcinoma↗
PubMed1989

Rats with mammary cancer treated with toremifene and interferon: morphometry and needle aspiration biopsy for determination of ATP and 14C-fluorodeoxyglucose content.

The combined and separate action of the antiestrogen toremifene (TOR) and recombinant rat gamma interferon (RIF) was studied in rat mammary cancer induced by dimethylbenzanthracene (DMBA). The content of ATP and 14C-fluorodeoxyglucose (FDG) was also determined from fine needle aspiration biopsies (FNAB). RIF alone had no antitumor activity, when measured as the average number of new tumors appearing in RIF and control animals (2.4 vs 2.4 new tumors per animal), while TOR and TOR + RIF had a significant effect (1.2, P less than 0.05 and 0.6, P less than 0.01). Morphometrically, there was a significant decrease in the amount of epithelium in the tumors of the RIF + TOR animals (65% vs 82% in the controls, P less than 0.05); there was conversely an increase in the stromal component (25% vs 14%, NS). It appears that an increase of the stromal compartment is part of the healing process. The feasibility of the FNAB-technique was shown by the finding that there was a close correlation between FDG and ATP content in almost all the groups before and after treatment. Thus, FDG and ATP measure the same phenomenon, i.e., energy content. There was a large variation in the contents of ATP and FDG within and among the groups, which invalidated considerations regarding the predictive value of ATP and FDG content in tumors subject to treatment.

Adenosine Triphosphate↗
PubMed1989

Biodistribution and scintigraphy of 11C-toremifene in rats bearing DMBA-induced mammary carcinoma.

A new antioestrogenic antitumour compound toremifene was labeled with 11C or 3H. The tissue distribution and tumour uptake of the compounds in DMBA induced breast tumour bearing rats was investigated. 11C-toremifene was localized by gamma camera scintigraphy and tissue counting. 3H-Toremifene was determined by liquid scintillation counting after oxidizing the tissue samples. Toremifene was distributed to several tissues due to the lipophilicity and was not taken up specifically by the tumours to any great extent. However, the radioactivity of the tumours increased as a function of time although it declined e.g. in the liver. The accumulation to the tumour was a slow process and cannot be followed up reliably by such short half-life radionuclides as 11C. The tumour uptake properties of toremifene resemble those of tamoxifen and several other oestrogen receptor binding compounds. These substances have limited use in diagnosing and imaging oestrogen receptor rich breast tumours in man.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Growth of human colorectal carcinoma implants in the mouse subrenal capsule assay.

The subrenal capsule assay (SRCA) in normal immunocompetent mice was performed from 1331 implants of 43 human colorectal carcinomas to evaluate the possible applications for clinical chemosensitivity testing. Also the effect of an immunosuppressive agent, cyclosporine, was tested on the growth of tumours. Histologically in all except one of 23 saline-treated tumours the original tumour tissue was replaced by granulation tissue and inflammatory cells. This was also true in cyclosporine-treated mice since in only one of the nine tests tumour cells were observed. The macroscopic growth of the implants in the cyclosporine-treated mice was significantly less than in the saline-treated mice. Flow cytometric DNA-analysis revealed that the difference between macroscopic growth of saline and cyclosporine-treated groups was observed only in DNA-diploid tumours. We conclude that new methods are required to preserve the viability of human colorectal carcinoma in the SRCA.

Animals↗
PubMed1988

Comparative double-tracer whole-body autoradiography: uptake of 11C-, 18F- and 3H-labeled compounds in rat tumors.

The uptake of various labeled compounds by tumors was studied by double-tracer whole-body autoradiography (DTWBA) in rats. Each animal carried two types of tumors: mammary carcinomas and the Walker 256 carcinosarcomas. The markers used were [18F]- and [3H]fluorodeoxyglucose (glucose utilization), [3H]thymidine (cell proliferation), [11C]methionine (amino acid metabolism) and [11C]- and [3H]toremifene (estrogen-receptor-avid agents). In each experiment, the distribution of a substance labeled with short-lived radionuclide (11C or 18F) was compared with that of another substance labeled with a long-lived nuclide (3H). Quantification was done by combining computerized image analysis of the autoradiograms with liquid scintillation counting of punched tissue pieces obtained from the cryosections. The relationships between the uptakes of the various radiopharmaceuticals were recorded in tumors and normal tissues. The dynamics of [18F]fluorodeoxyglucose and [11C]methionine were determined in tumors and some selected tissues by positron emission tomography (PET). The uptake rate between fluorodeoxyglucose and thymidine in the mammary tumor was five times higher than the ratio in the Walker tumor. The corresponding figure for FDG/methionine was four times. Thymidine, compared with methionine, was twice as efficient. Thus, the mammary tumors were best imaged with FDG or thymidine. The non-steroid antiestrogen toremifene was taken up in very low amounts by these tumors. By DTWBA, experimental tumors may serve as their own control.

Animals↗
PubMed1988

Binding of toremifene to human serum proteins.

The in vitro protein binding of toremifene in human serum was measured by ultracentrifugation using 3H-toremifene together with unlabeled toremifene, 50, 500, and 5000 ng/ml. Of the total radioactivity 99.7 per cent was bound to the proteins independent of the concentration of the unlabeled drug. Binding of toremifene to different protein fractions was studied by adding 3H-toremifene and 500 ng/ml of cold toremifene to normal serum. The serum samples were exposed to agarose gel electrophoresis to fractionate different proteins. The radioactivity was localized using a position-sensitive proportional counter. After that the proteins were visualized by staining. Of the total protein bound radioactivity 92 per cent was bound to albumin, about 6 per cent to beta 1 globulin fraction and about 2 per cent to a fraction between albumin and alpha 1 globulins, part of this probably to alpha 1 acid glycoprotein.

Blood Proteins↗
PubMed1988

The significance of estrogen receptors in tamoxifen and toremifene therapy.

Estrogen receptor (ER) concentration of breast cancer tissue is important in predicting the response of each patient to hormonal, especially antiestrogen treatment. About half of the patients with ER rich tumours respond and only about 10% of the patients with ER poor tumours respond to antioestrogen treatment. Tamoxifen is a well known and widely used drug. Toremifene is a new antioestrogen, developed in Finland. At standard doses both compounds have comparable hormonal and antitumour effects, and there is no clear difference between the compounds in the affinity to ER. The value of ER in predicting the response to tamoxifen and toremifene therapy in ER positive breast cancer is significant. It is not known, however, if the role of ER remains the same with high dose toremifene. Although ERs are an important predictive factor, the antioestrogens evidently act through them only in part. As the prediction is correct in about half of the patients, other mechanisms must influence tumour growth regulation, such as the expression of oncogenes and the synthesis and activity of growth factors.

Breast Neoplasms↗