Quantitative studies of ductal versus alveolar differentiation from rat mammary clonogens.

In a program aimed at defining and characterizing the cellular origins of radiogenic mammary cancer, we developed and have used a quantitative rat mammary cell transplantation model to investigate hormonal control of differentiation, growth, and response to ionizing radiation. In this model, in response to appropriate hormonal stimulation, a subpopulation of transplanted mammary epithelial cells gives rise to either alveolar colonies (AU) or ductal colonies (DU). The cumulative data support the conclusion that both types of colonies are derived from single clonogenic mammary cells.

Extended culturing of androgen-responsive human primary epithelial prostate cell isolates by continuous treatment with interstitial collagenase.

Continuous culturing of two distinct human prostate specimens in the presence of interstitial collagenase added directly to conventional medium resulted in the isolation and extended growth of primary epithelial prostate cell (PEPC) cultures from each. Both continued to proliferate substantially beyond the average time determined for analogous untreated epithelial prostate isolates. Both repeatedly stain positive for keratin and are characteristically epithelial in morphological appearance and growth model.

Use of a DNA microfluorometric assay to measure proliferative response of mink lung cells to purified TGF beta and to TGF beta activity found in prostate cell conditioned medium.

The proliferative response of Mv1Lu cells to purified TGF beta 1, or TGF beta-like activity released by various cells into medium conditioned over a 24-h period was quantitated by adapting a rapid DNA fluorometric assay. Acid activation of the conditioned medium allowed the amount of biologically latent versus active TGF beta to be quantitated. A neutralizing antibody specific for TGF beta 1, 1.

Quantifying the frequency of radiogenic thyroid cancer per clonogenic cell in vivo.

We used quantitative cell transplantation to evaluate the frequencies of the formation of radiogenic thyroid cancer per clonogenic rat thyroid epithelial cell in vivo. Irradiation of thyroid cells with 5 Gy 137Cs gamma rays before transplantation significantly increased the incidence of thyroid carcinoma formation in such grafts compared to similar grafts of unirradiated thyroid cells. We calculated the frequencies of radiogenic cancer by subtracting cancer incidences in unirradiated groups from incidences in irradiated groups and dividing by the number of clonogens grafted.

Characteristics of the glutathione/glutathione-S-transferase detoxification system in melphalan resistant human prostate cancer cells.

Glutathione (GSH) and glutathione-S-transferases (GST) have been implicated in resistance of tumor cells to certain alkylating agents, including melphalan. Glutathione levels and GST activities were determined in melphalan-resistant sublines of the human prostate carcinoma cell lines DU 145, PC-3 and LNCaP produced by serial treatment with melphalan at progressively increasing concentrations. The resistant sublines M4.

A retrospective review of nodal treatment for vulvar cancer.

From 1983 to 1990, 42 clinical N0, N1 patients with invasive squamous cell carcinoma of the vulva underwent surgery for the primary cancer, followed by nonrandomized assignment to either surgery or radiation therapy for nodal management. This is a retrospective analysis reviewing treatment outcome and complications of inguinofemoral dissection versus photon irradiation. Group I (N = 24) underwent either bilateral or unilateral inguinofemoral dissection; Group II (N = 18) underwent bilateral groin irradiation.

Effects of suramin on the proliferation of primary epithelial cell cultures derived from normal, benign hyperplastic and cancerous human prostates.

Primary epithelial cultures (PECs) derived from normal, benign hyperplastic (BPH), and cancerous human prostate tissue were treated with increasing doses of suramin, and assayed for cell proliferation over a period of days. The suramin IC50 (inhibitory concentration 50%) value was 0.5 to 1.

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

Purpose: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam).

Patients And Methods: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER).

Phase II trials of interferons-alpha and -beta in advanced sarcomas.

Interferons (IFNs)-alpha and -beta were administered to patients with metastatic sarcomas in two different Eastern Cooperative Oncology Group studies. In one study, patients received IFN-alpha 2b, 20 million units/m2 i.v.

Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma.

Background: Interferon alfa has been found to be effective as an antitumor agent (with a response rate of 30 percent) in patients with low-grade non-Hodgkin's lymphoma, but its effectiveness in those with intermediate-grade non-Hodgkin's lymphoma has been less adequately tested. In a prospective randomized study we evaluated the effectiveness of adding interferon alfa to cytotoxic chemotherapy in patients with clinically aggressive, low-grade non-Hodgkin's lymphoma and certain histologic variants of intermediate-grade non-Hodgkin's lymphoma, not including diffuse histiocytic lymphoma.

Methods: The patients were randomly assigned to a regimen of cyclophosphamide, vincristine, prednisone, and doxorubicin or to this regimen combined with recombinant interferon alfa.

Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days.

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity in in vitro and in in vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study.

Antilymphoma activity of human gamma delta T-cells in mice with severe combined immune deficiency.

Human Burkitt lymphoma (Daudi) cells grow as disseminated tumors in mice with severe combined immune deficiency (SCID) after either i.v. or i.

The strategic use of antiestrogens to control the development and growth of breast cancer.

Tamoxifen has become the endocrine treatment of choice for all stages of breast cancer. Its low incidence of side effects and proven survival advantage observed during adjuvant therapy in postmenopausal women with node-positive disease has encouraged the use of long-term treatment for patients to benefit fully from therapy. The drug has an appropriate level of estrogen-like effects that could be beneficial to maintain bone density and prevent development of coronary heart disease by lowering circulating cholesterol.

The effects of goitrogenesis, involution, and goitrogenic rechallenge on the clonogenic cell content of the rat thyroid.

A fraction of enzymatically monodispersed rat thyrocytes from untreated animals clonally proliferate into thyroid follicular units following transplantation into the subcutaneous fat pads of syngeneic recipients. During the induction of experimental goiters in rats either with 3-amino-1,2,4-triazole/iodine sufficient diet or KClO4/Remington low iodine diet, the clonogenic fractions of cells from aminotriazole goiters decreased to 1.9 x 10(-4) and KClO4 goiters to 9.

Trimetrexate in advanced renal cell carcinoma. An ECOG phase II trial.

Thirty-four chemotherapy-naive, ambulatory patients with advanced renal cell cancer were treated with the non-classical antifol trimetrexate at the intravenous dose of 12 mg/m2 daily x 5 every three weeks (8 mg/m2 qd x 5 for greater than 30% bone marrow previously irradiated). One patient experienced a partial response lasting 24 weeks for a response rate of 3% (exact 95% CI, 0.1 to 15.

Chromosome losses in tumorigenic revertants of EJ/ras-expressing somatic cell hybrids.

Tumorigenic transformation of SV40-immortalized human uroepithelial cells (SV-HUC) after transfection with EJ/ras was previously reported to be a rare event. To test the hypothesis that ras transformation requires loss of suppressor genes, somatic cell hybrids were generated between a rare tumorigenic transformant and an isogeneic nontumorigenic EJ/ras transfectant obtained in the same experiment. Both parental cell lines, as well as all hybrid progeny, expressed mutant p21 ras protein, but injections of three such independent hybrids into athymic nude mice at passage (P) 4 demonstrated that tumorigenicity was suppressed at 20 of 22 sites.

Levels of colorectal ornithine decarboxylase activity in patients with colon cancer, a family history of nonpolyposis hereditary colorectal cancer, and adenomas.

Ornithine decarboxylase (ODC), a key enzyme in mammalian polyamine biosynthesis, has been proposed to be a marker of colonic epithelial cell proliferation and risk for colorectal cancer. We investigated the basal levels of ODC activity in sigmoid and rectal mucosae, and basal and tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced levels of skin ODC activity in individuals with a personal history of colon cancer (n = 9 colon; n = 58 skin), a family history of nonpolyposis hereditary colorectal cancer (n = 49; n = 42), adenomas (n = 16; n = 40), and healthy, family history-negative control subjects (n = 40; n = 79). Using a fresh tissue assay and samples obtained after a standard colon lavage preparation, colon mucosal ODC levels ranged from 0 to 192 pmol/mg/h (sigmoid, 0-163 pmol/mg/h; mean, 36 +/- 32 pmol/mg/h; rectum, 0-192 pmol/mg/h; mean, 35 +/- 32 pmol/mg/h).

Antithrombin III level, fibrinogen level, and platelet count changes with adjuvant tamoxifen therapy.

Adjuvant therapy for breast cancer with tamoxifen is suggested to be of benefit to both women with negative and women with positive axillary nodes, and treatment lasting several years is currently being investigated. Venous thrombophlebitis may complicate tamoxifen treatment at a rate of approximately one per 800 treatment-years. To explore the possible mechanisms of this effect, we evaluated changes in antithrombin III levels, fibrinogen levels, and platelet counts in 140 postmenopausal women with surgically resected breast cancer who were disease free and participating in a double-blind, placebo-controlled, randomized toxicity study of tamoxifen.

Comparison of spontaneous mutagenesis in early-passage human mammary cells from normal and malignant tissues.

Spontaneous mutant frequencies were determined in early-passage epithelial-cell strains derived from either normal or malignant human breast tissues, as well as a non-tumorigenic immortalized human mammary epithelial cell line (184B5) derived from normal cells. Mutations at the hypoxanthine-guanine phophoribosyltransferase (HPRT) locus were quantified by determining the 6-thioguanine resistance. Mutant frequencies in human mammary epithelial cells (HMEC) from 4 normal and 5 carcinoma tissue samples did not differ significantly.

Clinical and biologic effects of combination therapy with gamma-interferon and tumor necrosis factor.

Tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN) are cytokines with synergistic biologic and antiproliferative effects in vitro and in mouse models. The biologic effects of the combination of TNF and gamma-IFN, however, have not been studied well in humans. A Phase I trial was conducted of TNF and gamma-IFN therapy in 24 patients with advanced malignancies to determine the tolerability of the combination and the biologic effects of TNF and gamma-IFN in vivo.

The plateau phase rat goiter contains a sub-population of TSH-responsive follicular cells capable of proliferation following transplantation.

In the rat, chronic TSH stimulation leads to self-limited thyroid hyperplasia, goitrogenesis, and TSH-responsive thyroid tumors. The current studies were aimed at clarifying the mechanism by which hormone-responsive, proliferating follicular cells arise in quiescent plateau phase rat goiters. Enzymatically monodispersed rat thyrocytes from early plateau phase and involuting goiters were analyzed for the capacity to form thyroid follicular units after transplantation into syngeneic recipients.

A phase I trial of 5-fluorouracil, leucovorin, and dipyridamole given by concurrent 120-h continuous infusions.

A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m2 daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated.

Loss of local control with prolongation in radiotherapy.

Twelve published clinical results of radical radiotherapy of head and neck cancer have been reviewed, seven of them with fresh multivariate analyses, to determine the magnitude of time factors relating local control to overall time. In all but two of the data sets a significant loss of local control was observed with prolongation. The median rate of loss was 14% in only 1 week, the range 3 to 25%.