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Biomedical subjects

C K Osborne

Publications and source records attributed to C K Osborne.

At least 145 records · Page 8Linked to original sources
PubMed1989

Pain control in breast cancer. A panel discussion.

Pain can be a prominent finding in breast cancer patients. It may occur in the setting of the postmastectomy period, related to the disruption of normal neural pathways or the development of lymphedema. In advanced disease, the management of pain from nerve compression or bone metastases requires special approaches. In this panel discussion, the participating physicians will discuss these topics and provide an up-to-date approach to pain control in breast cancer patients.

Analgesics, Opioid↗
PubMed1989

Cell proliferative indices and DNA content as prognostic factors in primary breast cancer.

Cumulative data from several studies suggest that indices of cell proliferation, including tritiated thymidine labelling index, S-phase fraction and DNA ploidy are among the most powerful prognostic factors in patients with breast cancer. If the prospective trials currently in progress confirm these findings, then DNA flow cytometry may become standard in the management of breast cancer patients, particularly in selecting those node-negative patients who have a relatively high risk of relapse and who may benefit from adjuvant systemic therapy.

Breast Neoplasms↗
PubMed1989

Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice.

Insulin and insulin-like growth factors (IGIs) stimulate the growth of human breast cancer cells in vitro. The type I somatomedin receptor (SR) expressed in these cells may mediate the growth effects of these peptides. We have examined the role of this receptor on human breast cancer growth with a monoclonal antibody (alpha-IR-3) that blocks the receptor binding domain and inhibits IGF-I-induced growth. alpha-IR-3 inhibited clonal growth in vitro and blocked the mitogenic effect of exogenous IGF-I in both MCF-7 and MDA-231 breast cancer cell lines. Antibody-induced blockade of the type I SR also inhibited the estrogen-independent MDA-231 cells growing in vivo in nude mice, but growth of the estrogen-dependent MCF-7 cells was unaffected. IGIs are important growth regulators of MDA-231 breast cancer cells. Blockade of this growth stimulatory pathway may provide a new treatment strategy.

Animals↗
PubMed1989

Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens.

In a prior National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant study, the addition of the antiestrogen tamoxifen to chemotherapy with melphalan and fluorouracil adversely affected survival in several patient subsets, suggesting an antagonistic drug interaction. To investigate this possibility, we studied the interaction of tamoxifen and other antiestrogens with several cytotoxic drugs in cultured human breast cancer cell lines. Clinically relevant concentrations of tamoxifen and melphalan reduced colony survival of estrogen receptor (ER)-positive breast cancer cells when used alone in a colony-forming assay. However, pretreatment of cells with tamoxifen followed by exposure to melphalan resulted in antagonism, with more colonies surviving treatment with the combination than with melphalan alone. Identical effects were seen using several other triphenylethelene antiestrogens. An antagonistic interaction was observed even with a brief preincubation with tamoxifen that had no effect on cell proliferation, indicating that antagonism was not due to tamoxifen's known cell kinetic effects. Tamoxifen even antagonized melphalan cytotoxicity in ER-negative breast cancer cells and in cultured liver cells. An additive drug interaction occurred when melphalan was combined with pharmacologic concentrations of estradiol or medroxyprogesterone acetate, but antagonism was also observed with dexamethasone. Tamoxifen also antagonized the cytotoxicity of fluorouracil in these cells. However, an additive interaction occurred when the antiestrogen was combined with doxorubicin or 4-hydroxy-cyclophosphamide, an alkylating agent that is transported into the cell by a different carrier-mediated mechanism than melphalan. To avoid potential antagonism in the clinic, combinations of tamoxifen with melphalan and/or fluorouracil should be avoided.

Breast Neoplasms↗
PubMed1989

Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Age Factors↗
PubMed1989

Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor.

Insulin-like growth factor-II (IGF-II) is a potent mitogen for several types of cultured cells and tissues. We have studied the interaction of IGF-II with a panel of cultured human breast cancer cell lines, examining the possibility that these cells synthesize and secrete IGF-II activity which could have autocrine/paracrine functions. Synthetic IGF-II was mitogenic in five of seven cell lines tested, including the estrogen receptor-positive lines MCF-7L, ZR75-1, and T47D and the estrogen receptor (ER)-negative lines Hs578T and MDA-231. IGF-II was slightly less potent than IGF-I in stimulating DNA synthesis in MCF-71 cells, an effect that paralleled its ability to compete for [125I]IGF-I binding in these cells. Affinity labeling studies revealed that IGF-II could also compete for binding to the 130,000 mol wt alpha-subunit of the IGF-I receptor. A monoclonal antibody to the IGF-I receptor inhibited the mitogenic effects of IGF-II in MCF-7L and MDA-231 cells, suggesting that this receptor mediates the growth effects of IGF-II in these breast cancer cells. Using a RIA and a RRA, IGF-II-like activity was detected in conditioned medium extracts processed to remove IGF-binding proteins from several breast cancer cell lines, with the highest levels found in conditioned medium from MCF-7L and T47D cell lines. IGF-II mRNA transcripts in MCF-7L and T47D cells were identified by Northern blot analysis and were confirmed by RNase protection assay. IGF-II mRNA was increased by estrogen in MCF-7L cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1989

Prognostic factors in breast cancer.

A variety of tumor characteristics can provide prognostic information useful in managing the patient with primary breast cancer. Some of these characteristics are firmly established, whereas others are observer dependent or require prospective validation. No single characteristic, however, is likely to fully define which patient with primary breast cancer is destined to relapse. This clinical dilemma--recognition of the high-risk patient--is particularly important in the management of women with node-negative breast cancer. Because most women with this early stage of disease will be cured by surgery alone, the use of adjuvant chemotherapy must be limited to high-risk subsets. Tumor size and ER status are established prognostic factors. Histologic and nuclear grade may be important, but problems of interobserver variability remain. Some studies have shown that aneuploidy or a high S-phase fraction may be independent, high-risk characteristics. Flow cytometric DNA content analysis must be applied with caution, however, because the calculation of S-phase fraction has not been standardized and because the prognostic utility of this approach has not been prospectively confirmed. For now, a prudent approach might be to gather as much prognostic information about each patient's tumor as possible. Those with several of the high-risk characteristics listed in Table 2 should receive strongest consideration for adjuvant treatment. Some of these same prognostic factors, along with several others, can be used to characterize the high-risk node-positive patient. The number of involved axillary nodes is the most important established predictor. Progesterone-receptor status is associated with both disease-free and overall survival, whereas ER status is independently related only to overall survival. Histologic grade, DNA ploidy, and S-phase fraction can also be used to help define the high-risk patient. Finally, tumors that amplify or overexpress the HER-2 gene may have a higher risk of relapse, although this finding has been questioned. Management of patients with breast cancer requires an individualized approach that is based on a careful weighing of a variety of prognostic considerations. The relative importance of these factors will require further large-scale, prospective, multiparameter studies. Although results from such studies are awaited, an understanding of the clinical heterogeneity of breast cancer must be based on a multiplicity of observations, each of which characterizes, in a limited way, the biology of this disease.

Axilla↗
PubMed1989

Effects of c-myc overexpression on the growth characteristics of MCF-7 human breast cancer cells.

Amplification and overexpression of the c-myc protooncogene have been observed in 22 to 32% of primary human breast cancers, yet the exact role of this gene in mammary tumor progression is unclear. We sought to elucidate this role by overexpressing cloned myc genes in the human breast carcinoma cell line MCF-7. We found that augmented myc RNA levels were associated with slower in vitro growth rates, but that estrogen receptor levels, the requirement for estrogen for in vivo growth in castrated athymic nude mice, and sensitivity to the antiestrogen, tamoxifen were not altered. Furthermore, chemosensitivity to the cytotoxic agent, Adriamycin, was not affected. Lastly, overexpression of a transfected myc gene did not suppress endogenous myc levels unlike the findings in lymphoma cells. Thus our data suggest that the effect of augmented myc expression in human breast cancer cells is complex and may not induce more malignant patterns of growth as has been suggested for other human cancers.

Animals↗
PubMed1989

Adjuvant treatment of node-negative breast cancer.

About half of all breast cancer patients do not have axillary nodal involvement at the time of diagnosis, and this fraction will become even larger as more women participate in screening mammography programs. Recently completed trails of limited surgery have changed the primary management of node-negative disease for many women. Now, early results from a number of carefully controlled clinical trails suggest ways in which the approach to adjuvant treatment of this disease can be improved.

Breast Neoplasms↗
PubMed1988

Immunoreactive alpha transforming growth factor activity in effusions from cancer patients as a marker of tumor burden and patient prognosis.

alpha Transforming growth factors (alpha-TGFs) are polypeptides that stimulate anchorage-independent growth of various nontransformed cells in vitro and are believed to be involved in autocrine stimulation of tumor cells. alpha-TGF activity is secreted by a variety of human cancers leading to the possibility that it may serve as a tumor marker. alpha-TGF activity was measured in 130 effusions from patients with various types of cancer with a radioimmunoassay using sheep antibodies against the C-terminal 17 amino acids of linear rat alpha-TGF. Forty-two % of the effusions contained immunoreactive alpha transforming growth factor (Ir-alpha-TGF) activity, including 13 of 34 (38%) breast cancer, 12 of 24 (50%) lung cancer, and 13 of 31 (42%) ovarian cancer specimens. Concentrations ranged from 1.56 to 50 ng/ml. Only 3 of 17 control effusions from noncancer patients had low levels of activity, all less than 2 ng/ml. The presence of Ir-alpha-TGF activity correlated with patients' performance status (PS) and tumor burden. It was present in 18 of 67 (27%) effusions of patients with PS less than or equal to 2 and in 23 of 33 (70%) with PS 3 or 4 (P less than 0.0001). Only 2 of 43 (4%) patients with one site of metastatic disease had detectable Ir-alpha-TGF (mean, 0.23 ng/ml); 18 of 37 (48%) with two sites (mean, 5.22 ng/ml, P less than 0.0001); and 33 of 34 (97%) with greater than two sites (mean, 5.93 ng/ml, P = 0.002). It was present in a larger percentage of effusions from breast cancer patients with estrogen- and progesterone receptor-negative tumors. Univariate analysis revealed that detectable Ir-alpha-TGF activity, PS 3 or 4, and the number of sites of disease correlated with a shorter survival. Only Ir-alpha-TGF and PS 3 or 4 retained significance in a multivariate analysis. In conclusion, Ir-alpha-TGF is frequently detectable in effusions from cancer patients, it correlates with other known adverse prognostic factors, and its presence predicts for a poor survival. Further studies of alpha-TGF activity in more readily accessible body fluids such as serum or urine are warranted.

Ascitic Fluid↗
PubMed1988

Transforming growth factor beta: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells.

Transforming growth factor beta (TGF beta), a two-subunit Mr 25,000 polypeptide, inhibits growth of several epithelial human cancer cell lines and has been proposed as an autocrine growth inhibitor. TGF beta activity has been found in conditioned media from some breast cancer cell lines, and TGF beta mRNA has been detected in breast cancer cell lines and human breast cancer specimens. In the present study we attempted to characterize the interaction of TGF beta with breast cancer cells by examining the biological activity, receptor binding, and secretion of this polypeptide by a panel of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines. Growth of the four ER-negative lines, MDA231, MDA330, HS578T, and BT20, was exquisitely sensitive to TGF beta. Dose-dependent inhibition of monolayer growth, anchorage-independent growth, and of [3H]thymidine incorporation was observed with TGF beta concentrations ranging from 1 to 100 pM. Growth of the four ER-positive lines, T47D, ZR75-1, and two MCF7 lines from different laboratories, was unaffected by similar concentrations of TGF beta. In receptor-binding studies using 125I-TGF beta, the four ER-negative lines exhibited specific high affinity TGF beta receptors. Binding was a time- and temperature-dependent process. Scatchard analysis of the binding data showed between 2800 and 12900 receptor sites per cell and a Kd between 29 and 160 pM. Epidermal growth factor, insulin, insulin-like growth factors I and II, and transforming growth factor alpha did not compete for 125I-TGF beta binding. Chemical cross-linking studies with ER-negative breast cancer cells revealed three specific TGF beta receptors with molecular weights approximating 400,000, 92,000, and 69,000. The four ER-positive lines had no detectable TGF beta binding. Using a radioreceptor assay with A549 cells and a NRK bioassay, TGF beta activity was detectable in the conditioned media from the four ER-negative cell lines; media from the ER-positive lines had low levels of TGF beta activity. In summary, ER-negative, estrogen-independent cultured human breast cancer cells have receptors for, are inhibited by, and secrete TGF beta activity, suggesting the possibility that this polypeptide may function as an autocrine growth inhibitor or as a paracrine growth factor for tumor stromal cells.

Affinity Labels↗
PubMed1988

Secreted growth factors from estrogen receptor-negative human breast cancer do not support growth of estrogen receptor-positive breast cancer in the nude mouse model.

Estrogen receptor (ER)-negative MDA-231 human breast cancer cells have been shown to secrete high concentrations of several growth factors including transforming growth factor-alpha and insulin-like growth factor I, which could have important autocrine or paracrine growth regulatory functions and, additionally, could explain the rapid autonomous growth of these cells. In contrast, the hormone-responsive, ER-positive MCF-7 cells secrete low levels of these factors constitutively. Since estrogen treatment increases secretion of these growth factors in MCF-7 cells, it has been postulated that these growth factors mediate estrogen's growth effects through an autocrine mechanism. To test this hypothesis we reasoned that growth factors supplied by MDA-231 cells should support growth of MCF-7 cells in an estrogen-depleted environment. Inoculation of castrated female athymic nude mice with MDA-231 cells resulted in rapid tumor growth. However, MDA-231 tumors did not support growth of MCF-7 cells inoculated on the opposite flank by an endocrine mechanism; MCF-7 tumors required estrogen supplementation for growth. To determine if MDA-231 cells could support MCF-7 growth by a paracrine mechanism, various mixtures of the two cell lines were coinoculated at the same site in castrated or in estrogen-supplemented mice. ER was not detectable in tumors derived from a mixed inoculum, indicating the absence of MCF-7 cell growth. Furthermore, DNA flow cytometry of these tumors revealed only a single G1 peak representative of MDA-231 cells in estrogen-deprived mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Blockade of the epidermal growth factor receptor inhibits transforming growth factor alpha-induced but not estrogen-induced growth of hormone-dependent human breast cancer.

Transforming growth factor alpha (TGF alpha), a polypeptide that binds to the epidermal growth factor (EGF) receptor, is expressed and secreted by human breast cancer cells and has been proposed as an autocrine growth factor and as a mediator of the mitogenic effect of estrogen. We investigated the potential importance of secreted TGF alpha in estrogen-responsive MCF-7 human breast cancer cells using monoclonal (528ab and 225ab) and polyclonal antibodies that block the EGF/TGF alpha receptor. Confirming other studies, these MCF-7 cells expressed TGF alpha with mRNA transcripts of 4.8 kilobases identified by Northern analysis, and they secreted TGF alpha activity measured by normal rat kidney colony-forming assay and an EGF RRA of conditioned medium. This activity was increased 3-fold by 1 nM 17 beta-estradiol and decreased by 1 microM tamoxifen. 528ab and 225ab bound to EGF receptors in MCF-7 cells with high affinity [dissociation constant (Kd) 0.1-0.5 nM] and blocked the binding of EGF/TGF alpha. These antibodies failed to inhibit baseline DNA synthesis or growth of MCF-7 cells although they were potent inhibitors of EGF/TGF alpha-induced growth of these cells. We hypothesized that if secreted TGF alpha mediates estrogen-induced growth, then EGF/TGF alpha receptor blockade should inhibit estrogen stimulation. MCF-7 cells were first treated with tamoxifen to inhibit growth and to reduce TGF alpha expression. Under these conditions, estrogen replenishment induced a marked dose-dependent rescue of TGF alpha secretion, DNA synthesis, and cell proliferation. Exogenous TGF alpha also partially restored growth of tamoxifen-inhibited cells. Although the simultaneous addition of 528ab or 225ab blocked TGF alpha-induced rescue of MCF-7 cells, it had no effect on rescue by estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1987

Serum tamoxifen concentrations in the athymic nude mouse after three methods of administration.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. We have examined the steady-state serum tamoxifen concentrations achieved in mice with s.c. slow-release pellets, s.c. injections, and i.p. injections, in an attempt to identify a method that would yield serum levels similar to those observed in patients receiving tamoxifen therapy. Tamoxifen and tamoxifen metabolites were examined by a high-performance liquid chromatography assay which has a sensitivity of 8 ng/ml. Tamoxifen metabolites were not observed with any dose or schedule. After slow-release pellets containing 5 or 25 mg tamoxifen no tamoxifen was detectable, even after 2 weeks of treatment. Very low levels (0.07 microM) were found with 50-mg pellets. Tamoxifen was also not detected either with daily s.c. injections of 500 micrograms/mouse or with i.p. injections of 2.5 mg/kg. However, daily s.c. injections of 1000 micrograms or i.p. injections of 25, 50, or 100 mg/kg resulted in tamoxifen concentrations ranging from 0.21 to 0.51 microM which are similar to those observed in patients. Thus, clinically relevant tamoxifen concentrations can be achieved in the nude mouse with either of these methods of administration.

Animals↗
PubMed1987

Endocrine therapy of human breast cancer grown in nude mice.

Although there have been extensive studies of rodent breast tumor models, and of human breast cancer cell lines in culture, there is still need for a human tumor model which can be manipulated experimentally but also provides a valid expression of the tumor cells in a host environment. Athymic nude mice bearing transplanted human breast tumors have been proposed as such a model. This review therefore discusses the use of the athymic nude mouse model of the study of human breast cancer biology, and focuses on four subjects: 1. biological characteristics of heterotransplanted breast tumors; 2. endocrinology and pharmacology of hormonal agents in the nude mouse; 3. endocrine sensitivity of heterotransplanted tumors; and 4. applicability and limitations of this model for the study of human breast cancer.

Animals↗