Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice.

The non-steroidal antiestrogen tamoxifen (TAM) is successfully used to treat all stages of breast cancer in both pre- and postmenopausal women. Unfortunately, most women treated with TAM eventually develop resistant tumor recurrences which require intervention with a second-line endocrine therapy, or cytotoxic chemotherapy if the recurrence is completely endocrine insensitive. There is evidence that some recurrences may in fact be TAM stimulated.

Protein S and protein C level changes with adjuvant tamoxifen therapy in postmenopausal women.

Tamoxifen citrate is a synthetic antiestrogen that provides survival benefit when given as adjuvant treatment in postmenopausal women with breast cancer. Venous thrombophlebitis may complicate tamoxifen treatment at a rate of approximately one per 800 treatment-years. To explore the possible procoagulant effects associated with tamoxifen therapy we evaluated changes in protein S and C activity levels in 58 postmenopausal women with surgically resected breast cancer who were disease-free and participating in a double-blind, placebo-controlled, randomized toxicity study of tamoxifen.

Trimetrexate in advanced hormone-refractory prostate cancer. An ECOG phase II trial.

The antitumor activity and toxicity of trimetrexate (TMTX) was evaluated in measurable, hormone-refractory, advanced prostate cancer patients. Patients were required to have an ECOG performance status < 3, bidimensionally measurable disease, serum creatinine < or = 1.5 mg/dL, normal bone marrow function, and adequate hepatic function.

Up-regulation of gamma-glutamylcysteine synthetase activity in melphalan-resistant human multiple myeloma cells expressing increased glutathione levels.

Levels of intracellular glutathione (GSH) and the GSH-related enzymes gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyltranspeptidase (gamma-GT) were measured in the melphalan-resistant human multiple myeloma cell line 8226/LR-5 and were compared to those measured in the drug-sensitive 8226/S and doxorubicin-resistant 8226/Dox40 cell lines. Both GSH and gamma-GCS activity, the rate-limiting step in the de novo synthesis of GSH, were elevated by a factor of approximately 2 in the melphalan-resistant 8226/LR-5 cells relative to the other two lines. gamma-GT activity was not elevated significantly in the /LR-5 cells.

Hepatocellular carcinoma in the very elderly: to treat or not to treat?

We report a case of a patient with hepatocellular carcinoma (HCC) who has two unusual features. The patient was 95 years old at the time of diagnosis and his excellent response to treatment. The authors briefly review the age distribution of HCC and the treatments used.

Primary culture of flow cytometry-sorted rat mammary epithelial cell (RMEC) subpopulations in a reconstituted basement membrane, Matrigel.

We studied the growth of rat mammary epithelial cell (RMEC) subpopulations cultured in Matrigel. Mammary glands were removed, minced, and enzymatically dispersed. Mammary organoids (ductal and endbud fragments) were collected, enzymatically monodispersed, filtered, and labeled with fluorescein isothiocyanate-peanut agglutinin (PNA) and phycoerythrin-anti-Thy-1.

Recent trends in breast cancer incidence, mortality, and mammography.

The recent trends in mammography, and in breast cancer incidence and mortality, demonstrate the impact of an effective cancer control effort. The number of women over age 40 years who have ever had mammography has increased over 200% since 1980. Concomitantly, breast cancer incidence has increased about 32%, with nearly all of the increase in early stage disease.

Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies.

Purpose: To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF.

Patients And Methods: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 micrograms/kg once or twice daily) was administered on days 2 to 14.

Regulation of the levels of three transforming growth factor beta mRNAs by estrogen and their effects on the proliferation of human breast cancer cells.

Transforming growth factor (TGF) beta is a potent regulator of cell proliferation and may play a role in breast cancer cell growth. We have evaluated the regulation of TGF beta 1, TGF beta 2, and TGF beta 3 mRNAs by 17 beta-estradiol (E2) and 4-hydroxytamoxifen (MOH) in estrogen receptor-positive (ER(+)) MCF-7 and estrogen receptor-negative (ER(-)) MDA-MB-231 human breast cancer cells. We also determined the effect of TGF beta 1, TGF beta 2, and TGF beta 3 on the proliferation of these cells.

New approaches to cell kinetics in human tumors.

Both clinical and laboratory evidence indicate that local control rates for many experimental and clinical human tumors decrease with protraction of the overall duration of radiation therapy. A likely basis for this is tumor cell repopulation during treatment. Such observations have stimulated interest in tumor kinetics, and a number of techniques have evolved to increase the potential for meaningful clinical study of the proliferative behavior of tumors.

Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients.

Purpose: The Eastern Cooperative Oncology Group (ECOG) entered 766 patients onto two prospectively randomized surgical adjuvant clinical trials for lymph node-positive breast cancer (T1-3N1M0). Ninety-five percent (n = 728) of eligible patients have complete information on the prognostic covariables under study (tumor necrosis [TN], tumor size, number of positive lymph nodes, age) and a median follow-up duration of 10.3 years.

High DNA content and prognosis in lymph node positive breast cancer. A case control study by the University of Leiden and ECOG. (Eastern Cooperative Oncology Group).

To investigate whether breast cancer cells with unusually high nuclear DNA content are associated with an adverse outcome, Eastern Cooperative Oncology Group investigators selected breast cancer trial patients who suffered an early death (ED) within two years after diagnosis to compare with other trial patients who had a survival of at least 7.5 years. Paraffin blocks of primary breast cancers were obtained from 93 evaluable patients who had been enrolled in two surgical adjuvant trials for lymph node positive (LN+) disease (T1-3N1M0).

Frequency and determinants of screening for breast cancer in primary care group practice.

Background: Many studies reporting the frequency of breast cancer screening have been based only on physician and patient surveys or on data from quality assurance studies and do not assess the reliability of information obtained from these various sources.

Methods: To obtain more complete data we studied mammography performed in a 3-year period, 1988 through 1991, in 24 nonacademic primary care group practices by both auditing the medical records and obtaining questionnaire responses from 1819 women aged 53 to 62 years and from their 98 physicians in the nonmetropolitan Midwest.

Results: Medical record data indicated that mammography was performed in all 3 years in 16.

Phase I clinical trial of carboplatin and 41.8 degrees C whole-body hyperthermia in cancer patients.

Purpose: To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial.

Patients And Methods: Thirty assessable patients with cancer refractory to conventional therapy were treated.

The effects of intermittent progesterone upon tamoxifen inhibition of tumor growth in the 7,12-dimethylbenzanthracene rat mammary tumor model.

The development of endometrial cancer is a potential risk during long-term tamoxifen therapy for breast cancer. In order to protect the uterus, progestin treatment has been proposed for these patients. However, within the 7,12-dimethylbenzanthracene-induced rat mammary model, progesterone is known to reverse the antitumor effects of tamoxifen.

Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.

Purpose: To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE).

Patients And Methods: A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment.

An appraisal of strategies to reduce the incidence of breast cancer.

The current focus of breast cancer research is to develop a novel strategy to prevent the disease. In this review a potential model of breast cancer development is proposed based upon the results of laboratory models of the induction of mammary carcinogenesis. It is clear that susceptibility to initiation occurs in young female animals, and a preventive strategy is more effective the sooner it is started after initiation occurs.

Modulation of proliferation kinetics in human squamous cell carcinomas of the head and neck.

Objective: Proliferation of tumor clonogens during a course of conventional head and neck radiotherapy serves to compromise ultimate tumor control. Biologic strategies that attempt to alter tumor proliferation kinetics using cytostatic or antiproliferative agents may therefore prove valuable by limiting tumor cell repopulation during therapy.

Design: Three human squamous cell carcinoma (SCC) cell lines, derived from primary head and neck cancers, have been characterized in vitro via flow cytometric analysis of proliferation kinetics, and in vivo via tumor xenograft growth evaluation in athymic mice.

Characterization of rat mammary epithelial cell subpopulations by peanut lectin and anti-Thy-1.1 antibody and study of flow-sorted cells in vivo.

A cell separation method was developed for studies of the growth kinetics of rat mammary epithelial cell (RMEC) subpopulations in grafts and in culture in vitro. By flow cytometry of RMEC stained with fluorescein isothiocyanate-peanut agglutinin and phycoerythrin-anti-Thy-1.1 monoclonal antibody, we could distinguish four cell subpopulations from primary cultures of 7- to 8-week-old F344 female rat mammary glands: both negative (B-), PNA+, Thy-1.

Estrogenic actions of RU486 in hormone-responsive MCF-7 human breast cancer cells.

Previously, we demonstrated that the progestin components (19-nortestosterone derivatives) in oral contraceptives are able to stimulate human breast cancer cell proliferation via an estrogen receptor (ER)-mediated mechanism. We now examine RU486, an antiprogestin, to determine whether it has estrogenic properties because it is also a 19-nortestosterone derivative. We found that RU486 stimulated the growth of MCF-7 human breast cancer cells at a concentration of 10(-6) M, which is similar to the pharmacological concentration (micromolar range) found in women taking RU486.

Investigation of the mechanism of tamoxifen-stimulated breast tumor growth with nonisomerizable analogues of tamoxifen and metabolites.

Background: The nonsteroidal anti-estrogen tamoxifen (TAM) is the front-line endocrine treatment for breast cancer, but disease recurrence is common. Treatment failure may occur because tumors become insensitive to TAM. Alternatively, resistance may occur because tumors become stimulated rather than inhibited by TAM.

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

Background: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice.

A risk-benefit assessment of tamoxifen therapy.

Tamoxifen is the endocrine treatment of choice for all women with hormonally responsive breast cancer. 30 years of experience in both the laboratory and clinical setting have shown tamoxifen to be an effective adjuvant treatment with minor short term adverse effects. However, as therapeutic use has extended to 5 years and beyond, and as clinical trials begin which will assess the effectiveness of tamoxifen as a preventive treatment, concern about possible long term adverse effects is justified.

Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation.