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Biomedical subjects

M E Lippman

Publications and source records attributed to M E Lippman.

At least 181 records · Page 10Linked to original sources
PubMed1987

Selecting initial therapy for invasive breast cancer.

The correct choice of therapy for localized breast cancer is controversial. A great many published clinical experiences, some of considerable size, have tended on the one hand to provide apparently contradictory information, and on the other hand to polarize views. A detailed consideration of the many clinical, pathologic, biochemical and kinetic prognostic variables which may bias such clinical experiences will be discussed. These may contribute to differing results from institutions apparently employing a single treatment plan. The prospectively randomized trials which have helped to establish the limits of acceptable therapy for localized breast cancer will also be reviewed together with comments on their limitations. Particular attention will be paid to National Surgical Adjuvant Breast Project (NSABP) trial B-06; the Milan Cancer Institute trial; and current National Cancer Institute (NCI) investigations. A thorough consideration of these issues should permit a more rational choice of primary treatment for patients with Stage I and Stage II breast cancer.

Breast Neoplasms↗
PubMed1987

Neoadjuvant chemotherapy in the combined modality approach of locally advanced nonmetastatic breast cancer.

We have treated 76 patients with locally advanced breast cancer, 31 with stage IIIA, 41 with stage IIIB, and 4 with stage IV disease, with primary induction chemotherapy including an attempted hormonal synchronization in 70 patients. All were treated to maximum objective clinical response before proceeding to any local therapy. Patients achieving a complete response with a negative repeat biopsy generally received radiation therapy while patients with residual disease, partial response (PR) or no change (NC) status received debulking surgery prior to radiation therapy. Regardless of response to induction chemotherapy, patients received at least 6 additional months of chemotherapy following local therapy. Initial doses of combination chemotherapy were escalated to targeted myelosuppression. The objective response rate to induction chemotherapy was 93% with 49% complete response (CR), 44% PR, and 7% NC. The median numbers of cycles of chemotherapy to achieve a CR, PR, or NC were 5, 3, and 5, respectively. Three patients who currently have PRs are still on chemotherapy with continued tumor regression. Of 37 patients achieving a CR to chemotherapy, 35 were assessed by biopsies to determine pathological evidence of response. Twenty-three of the 37 patients (62%) were proven to be complete responders with negative biopsies. Twenty-four patients have relapsed, 6 with stage IIIA, 16 with stage IIIB, and 2 with stage IV. Five patients have had locoregional relapses alone, 4 locoregional and distant, and 15 distant alone. Median time to progression is 35.9 months for stage IIIA and 34.2 months for stage IIIB. Median survival is 35.3 months for stage IIIB and is indeterminate for stage IIIA. This aggressive primary chemotherapy regimen with hormonal synchronization followed by local therapy appears to provide excellent local control and encouraging early results on systemic disease control.

Adult↗
PubMed1987

[125I]17-alpha-iodovinyl 11-beta-methoxyestradiol interaction in vivo with estrogen receptors in hormone-independent MCF-7 human breast cancer transfected with the v-rasH oncogene.

[125I]17-alpha-Iodovinyl 11-beta-methoxyestradiol [( 125I]MIVE2) has been evaluated as a potential radiotracer for the diagnostic imaging of estrogen receptor (ER)-positive human breast cancer. In vivo distribution experiments with athymic ovariectomized nude mice bearing human breast tumors revealed an apparent correlation between uptake of 125I-labeled compound and estrogen receptor concentration in the tumors. At 4 h after i.v. injection of [125I]MIVE2, HS578T (ER negative), ZR75-B (intermediate ER), and MCF-7ras (high ER) tumors accumulated 0.320 +/- 0.186, 0.679 +/- 0.467, and 2.6163 +/- 1.0121% injected dose/g, respectively. With coinjection of unlabeled 17-beta-estradiol, levels of radioactivity in MCF-7ras tumors were decreased to 0.4859 +/- 0.1424% injected dose/g, indicating a receptor-mediated process. Peak activity of radioligand in MCF-7ras tumors and uteri was observed at 2 h and was retained for the 8-h time course. Blood and nontarget tissue, such as muscle, revealed a rapid clearance of 125I-labeled compound by 8 h. Eight hours after injection, uterus and tumor-to-blood ratios were calculated to be 225 and 21, respectively. Also, MCF-7ras tumors were shown to accumulate 6.5-fold more radioactivity than muscle. These data suggest that [125I]MIVE2 has the capability of interacting specifically and with high affinity with estrogen receptors in human breast tumors in nude mice and may possibly be used for imaging receptor-positive tumors in breast cancer patients with very low serum estrogen levels. Selective uptake of compound in MCF-7ras tumors emphasizes the usefulness of an estrogen receptor-positive tumor model which has a unique ability to grow in a host system without circulating estrogens.

Animals↗
PubMed1987

Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells.

The hormone-dependent human breast cancer cell line MCF-7 secretes transforming growth factor-beta (TGF-beta), which can be detected in the culture medium in a biologically active form. These polypeptides compete with human platelet-derived TGF-beta for binding to its receptor, are biologically active in TGF-beta-specific growth assays, and are recognized and inactivated by TGF-beta-specific antibodies. Secretion of active TGF-beta is induced 8 to 27-fold under treatment of MCF-7 cells with growth inhibitory concentrations of antiestrogens. Antiestrogen-induced TGF-beta from MCF-7 cells inhibits the growth of an estrogen receptor-negative human breast cancer cell line in coculture experiments; growth inhibition is reversed with anti-TGF-beta antibodies. We conclude that in MCF-7 cells, TGF-beta is a hormonally regulated growth inhibitor with possible autocrine and paracrine functions in breast cancer cells.

Breast Neoplasms↗
PubMed1987

Growth regulation of human breast carcinoma occurs through regulated growth factor secretion.

We describe studies on human breast cancer in which it is shown that specific growth factors (IGF-I, TGF alpha, PDGF) are secreted by human breast cancer cells and likely to be involved in tumor growth and progression. These activities are regulated by estradiol in hormone-dependent breast cancer and secreted constitutively by hormone-independent cells. These growth factor activities can induce the growth of hormone-dependent cells in vivo in athymic nude mice. Hormone-dependent breast cancer cells also secrete TGF beta, a growth-inhibitory substance, when treated with antiestrogens. TGF beta functions as a negative autocrine growth regulator and is responsible for some of the growth-inhibitory effects of antiestrogens.

Animals↗
PubMed1987

Estrogen and oncogene mediated growth regulation of human breast cancer cells.

The mechanism of growth control in estrogen-dependent and -independent human breast cancer is not completely understood. We have used both hormonally responsive and unresponsive breast cancer cells in culture to study the role of estrogens, oncogenes, and growth factors in their malignant transformation. MCF-7, an estrogen-receptor containing cell line, requires estradiol for tumor formation in vivo and is growth stimulated by estradiol and growth inhibited by antiestrogens in vitro. The growth regulation of MCF-7 cells by estrogens and antiestrogens may be linked to changes in several growth-related enzymes and polypeptide growth factors. Growth-acting polypeptides that are estradiol-inducible include IGF-I, TGF-alpha, and PDGF. Induction of at least two growth-related enzymes, thymidine kinase and dihydrofolate reductase is by transcriptional regulation of their mRNAs. To understand the natural progression of human breast cancer, we have experimentally constructed a hormone-independent fully tumorigenic cell line from the non-tumorigenic MCF-7 cells by introduction of an activated oncogene, v-rasH, into these cells by DNA-mediated gene transfer. Acquisition of the activated ras gene confers hormone autonomy on the previously hormone-dependent tumorigenicity and results in upregulation in secretion of some of the growth factors in amounts compared to estradiol stimulation. The transfected cells also become refractory to growth regulation by estradiol and antiestrogens in culture, although estrogen responses persist. Hormone-independent breast cancer cells in culture show high constitutive growth factor secretion. Direct infusion of some of the authentic growth factors and medium conditioned by estrogen-independent cells into athymic ovariectomized mice suggests a direct involvement of some of the polypeptides in the in vivo progression of tumors by these cells. Thus, aberrant production of growth factors, triggered either by activated oncogenes and estrogen stimulation in hormone-dependent cells, or by increased constitutive production in hormone-independent cells may in an autocrine, paracrine, or endocrine manner be associated with neoplastic growth of breast cancer.

Animals↗
PubMed1987

Assay of mitogen-induced effects on cellular incorporation of precursors for scavenger, de novo, and net DNA synthesis.

In summary we have presented data on [3H]dThd incorporation into DNA for a positive and negative growth modulator. These data clearly do not correspond to those based on net DNA synthesis (ortho[32P]phosphate incorporation into purified DNA) and previous knowledge of the effects of these hormones on cell number and cellular DNA accumulation. The paradox was resolved by directly analyzing effects of hormones on de novo pyrimidine biosynthesis. E2 stimulated both de novo and scavenger pathways in the first wave of DNA synthesis and only de novo in the second (and subsequent) waves. In contrast, tam progressively inhibited de novo pyrimidine biosynthesis. These hormonal effects on intracellulr pyrimidine pool sizes rendered [3H]dThd incorporation data by itself uninterpretable. [3H]dThd is a useful measure of DNA synthesis only if verified by independent measures of net DNA synthesis for the same time course and treatment conditions. In addition it may prove beneficial in various experimental systems to develop direct assays of de novo pyrimidine biosynthesis to assess mitogen effects. The experiments presented may also prove to be useful in evaluating the effects of mitogens and antimitogens on cells synchronized in the cell cycle by any of a variety of means.

Acetates↗
PubMed1987

Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines.

We report that human breast cancer cells secrete a growth factor that is biologically and immunologically similar to platelet-derived growth factor (PDGF). Serum-free medium conditioned by estrogen-independent MDA-MB-231 or estrogen-dependent MCF-7 cells contains a mitogenic or "competence" activity that is capable of inducing incorporation of [3H]thymidine into quiescent Swiss 3T3 cells in the presence of platelet-poor plasma. In addition, the conditioned medium contains an activity that competes with 125I-labeled PDGF for binding to PDGF receptors on normal human fibroblasts. The secretion of PDGF-like activity by the hormone-responsive cell line MCF-7 is stimulated by 17 beta-estradiol. Like authentic PDGF, the PDGF-like activity produced by breast cancer cells is stable after acid and heat treatment (95 degrees C) and inhibited by reducing agents. The mitogenic activity comigrates with a material of approximately equal to 30 kDa on NaDodSO4/polyacrylamide gels. Immunoprecipitation with PDGF antiserum of proteins from metabolically labeled cell lysates and conditioned medium followed by analysis on nonreducing NaDodSO4/polyacrylamide gels identified proteins of 30 and 34 kDa. Upon reduction, the 30- and 34-kDa bands were converted to 15- and 16-kDa bands suggesting that the immunoprecipitated proteins were made up of two disulfide-linked polypeptides similar to PDGF. Hybridization studies with cDNA probes for the A chain of PDGF and the B chain of PDGF/SIS identified transcripts for both PDGF chains in the MCF-7 and MDA-MB-231 cells. The data summarized above provide conclusive evidence for the synthesis and hormonally regulated secretion of a PDGF-like mitogen by breast carcinoma cells. Production of a PDGF-like growth factor by breast cancer cell lines may be important in mediating paracrine stimulation of tumor growth.

Breast Neoplasms↗
PubMed1987

Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17 beta-estradiol or v-Ha-ras oncogene.

The MCF-7 human breast cancer cell line responds to estrogen stimulation in vitro by increased secretion of growth factors and proliferation and in vivo by tumor formation in the nude mouse. To test a possible role of growth factor secretion in expression of the tumorigenic phenotype, we stably transfected MCF-7 cells with the v-Ha-ras oncogene to produce the MCF-7ras cell line. The MCF-7ras cell line was tumorigenic in the absence of estrogens and secreted 3- to 5-fold elevated levels of a high molecular weight form of a type alpha transforming growth factor-like growth factor, type beta transforming growth factor, and insulin-like growth factor I. MCF-7ras cells, in contrast to MCF-7, were less sensitive to further growth stimulation by estrogen, type alpha transforming growth factor, and insulin-like growth factor I and showed little change in receptor levels for these hormones. Conditioned medium from MCF-7ras cells as well as two of its component growth factors (insulin-like growth factor I and type alpha transforming growth factor) replaced estrogen in stimulating MCF-7 colony formation in vitro. A coordinate increase in growth factor secretion by human breast cancer may contribute to its escape from estrogen dependence.

Breast Neoplasms↗
PubMed1987

Adjuvant chemotherapy in males with cancer of the breast.

Analysis of recurrence rates in male breast cancer (MBC) has suggested that tumor size and degree of axillary lymph node involvement carry the same prognostic implications as for breast cancer in women. A similar spectrum of antineoplastic agents appears active in both females and males. Based on reports of active adjuvant chemotherapy of women with breast cancer, we initiated a trial of adjuvant chemotherapy of MBC in July 1974. Twenty-four patients have been treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). All patients had nodal involvement (median three nodes positive; seven patients had a single positive lymph node). All patients began adjuvant therapy within 4 weeks of either a radical or modified radical mastectomy. No postoperative radiotherapy was given. Median potential follow-up is 46 months. Four patients have recurred, one each at 15, 45, 61, and 65 months following mastectomy; two are dead of metastatic disease. The five-year survival rate projected by actuarial means is in excess of 80% (95% confidence interval: 74-100%). Based on these data, this treatment is highly encouraging when compared to other forms of treatment reported in the literature in which 5-year disease-free survival rates are less than 30%. We conclude that adjuvant therapy of MBC with a CMF regimen is feasible and may be associated with substantial improvement in disease-free survival and overall survival.

Aged↗
PubMed1987

Controversies in the treatment of cancer of the breast.

There are many important controversial areas in the management of breast cancer. This chapter focuses on adjuvant hormonal and chemotherapy for early-stage breast cancer. Standard care for node-positive premenopausal women is chemotherapy. However, there are still unanswered questions revolving around the administration of the treatment such as optimal timing, treatment duration, specific drugs, and dose intensity. Also, the questions of adjuvant chemotherapy for postmenopausal women, adjuvant endocrine therapy, and therapy for node-negative women are reviewed.

Adult↗
PubMed1987

Epidermal growth factor receptor gene expression in estrogen receptor-positive and negative human breast cancer cell lines.

Expression of epidermal growth factor (EGF) receptor by human breast cancer tissues has an inverse relationship with expression of the estrogen receptor and may be associated with a poor clinical response. We have studied the regulation of EGF receptor expression in a series of human breast cancer cell lines with varying degrees of estrogen responsiveness. Three estrogen receptor-positive lines, MCF-7, ZR-75-1, and T47D, were found to have less than 70,000 EGF binding sites per cell by radioreceptor assay and were growth stimulated in vitro by EGF. Four estrogen receptor-negative lines, MDA-MB-231, Hs578T, EVSA-T, and BT-20, contained greater than 70,000 EGF binding sites per cell and showed no in vitro growth stimulation by EGF. In all cell lines EGF receptor number was correlated with the amount of EGF receptor protein and RNA. Differences in EGF receptor expression between the cell types was not due to amplification of the EGF receptor gene. Rather, variations in EGF receptor expression between lines were due, at least in part, to differences in the rate of EGF gene transcription as determined by nuclear run-off studies. Our data confirm the previously described inverse relationship between expression of EGF and estrogen receptors. We show here that the absence of estrogen receptor expression in human breast cancer cell lines is associated with higher levels of functional EGF receptor protein and mRNA.

Adenocarcinoma↗
PubMed1987

Preliminary results of a phase II trial for the treatment of metastatic breast cancer with 5-fluorouracil and leucovorin.

The active metabolite of FUra, 5-fluorodeoxyuridine monophosphate (5-FdUMP), requires the presence of reduced folates to form a covalent ternary complex with the target enzyme thymidylate synthase (TS). In vitro and in vivo studies have demonstrated a potentiation of the cytotoxic effects of FUra when combined with the reduced folate, leucovorin. We have applied this concept to the treatment of metastatic breast cancer in a phase II trial, as recent clinical studies on patients with colorectal carcinoma have suggested an enhanced efficacy for the combination of FUra plus leucovorin. Patients entered on the present study are undergoing treatment with a 5-day daily regimen of leucovorin (500 mg/m2, iv) followed by FUra (375 mg/m2, iv). Toxicity and response data are currently being collected on patients who have failed "standard" combination regimens that included FUra. In patients with accessible tumor, serial biopsies are being obtained during treatment with the combination of FUra and leucovorin and during therapy with FUra alone to assess the degree of 5-FdUMP binding to the target enzyme, TS, in the presence and absence of exogenously administered leucovorin. Preliminary results from the biochemical studies suggest an enhanced saturation of TS by the fluorinated pyrimidine when administered with leucovorin.

Adult↗