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Biomedical subjects

N Rosen

Publications and source records attributed to N Rosen.

At least 55 records · Page 3Linked to original sources
PubMed1996

Targeted therapy for prostate cancer: the Memorial Sloan-Kettering Cancer Center approach.

Carcinoma of the prostate represents a wide range of diseases with differing prognoses. A key to selecting treatment depends on the ability to predict the natural history of the disease for the individual. Thus far, non-hormonal approaches have not demonstrated a survival advantage in randomized comparisons and, clearly, innovative approaches are needed. The clinical trials program developed at Memorial Sloan-Kettering Cancer Center is based on specific manifestations and specific targets of the disease and the predicted prognosis, using prostate-specific antigen and acid phosphatase changes as biomarkers of progression and response. In patients with minimal disease who have received local treatments but progressed systemically, we are studying methods aimed at stimulating their immune systems either by nonspecific immunopotentiation or specific immunization to specific glycoprotein or carbohydrate targets on the cancer cells, or to anti-growth factor receptor antibody aimed at blocking the specific signalling pathways that contribute to hormonal failure. These and other approaches provide an opportunity to treat this disease while maintaining an acceptable quality of life for patients.

Animals↗
PubMed1995

Identification of a novel repressive element in the proximal lck promoter.

The T-cell-specific protooncogene lck, a src-related tyrosine kinase, is under the control of two promoters that give rise to transcripts differing only in their 5'-untranslated regions. The distal promoter is transcriptionally active in both peripheral and thymic T-cells, whereas expression of the proximal promoter is highest in developing thymocytes. The proximal promoter has also been shown to be selectively activated in a number of colon carcinoma cell lines. Approximately 570 base pairs of proximal promoter sequence is required for expression in both T-cells and colon carcinoma cell lines. Protein binding studies were initiated with an oligonucleotide homologous to a region that, when deleted, causes an increase in promoter activity in transgenic animals. Two proteins with approximate molecular masses of 35 and 75 kDa were found to bind to this region as determined by UV cross-linking studies. Absence of specific protein binding is correlated with a high level of proximal promoter expression. Competitive gel retardation analysis identified a 9-base pair binding site within the proximal lck promoter that is necessary for repression of transcription in cells that contain specific binding activity. Mutants of this binding site do not repress transcription. Repression does not occur in a cell line that expresses lck and lacks this activity. These data support the hypothesis that activation of lck transcription in colon carcinoma is due, at least in part, to the loss of a transcriptional repressor.

Base Sequence↗
PubMed1995

A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.

Farnesyl protein transferase (FPTase) catalyzes the first of a series of posttranslational modifications of Ras required for full biological activity. Peptidomimetic inhibitors of FPTase have been designed that selectively block farnesylation in vivo and in vitro. These inhibitors prevent Ras processing and membrane localization and are effective in reversing the transformed phenotype of Rat1-v-ras cells but not that of cells transformed by v-raf or v-mos. We have tested the effect of the FPTase inhibitor L-744,832 (FTI) on the anchorage-dependent and -independent growth of human tumor cell lines. The growth of over 70% of all tumor cell lines tested was inhibited by 2-20 microM of the FTI, whereas the anchorage-dependent growth of nontransformed epithelial cells was less sensitive to the effects of the compound. No correlation was observed between response to drug and the origin of the tumor cell or whether it contained mutationally activated ras. In fact, cell lines with wild-type ras and active protein tyrosine kinases in which the transformed phenotype may depend on upstream activation of the ras pathway were especially sensitive to the drug. To define the important targets of FTI action, the mechanism of cellular drug resistance was examined. It was not a function of altered drug accumulation or of FPTase insensitivity since, in all cell lines tested, FPTase activity was readily inhibited within 1 h of treatment with the inhibitor. Furthermore, the general pattern of inhibition of cellular protein farnesylation and the specific inhibition of lamin B processing were the same in sensitive and resistant cells. In addition, functional activation of Ras was inhibited to the same degree in sensitive and resistant cell lines. However, the FTI inhibited the epidermal growth factor-induced activation of mitogen-activated protein kinases in sensitive cells but not in two resistant cell lines. These data suggest that the drug does inhibit ras function and that resistance in some cells is associated with the presence of Ras-independent pathways for mitogen-activated protein kinase activation by tyrosine kinases. We conclude that FPTase inhibitors are potent antitumor agents with activity against many types of human cancer cell lines, including those with wild-type ras.

Alkyl and Aryl Transferases↗
PubMed1995

Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases.

Herbimycin A is an ansamycin antibiotic isolated as an agent that reverses morphological transformation induced by v-src. Although herbimycin A is widely used as a tool for inhibiting multiple tyrosine protein kinases and tyrosine kinase-activated signal transduction, its mechanism of action is not well defined and includes a decrease in both tyrosine kinase protein levels and activity (Uehara, Y., Murakami, Y., Sugimoto, Y., and Mizuno, S. (1989) Cancer Res. 49, 780-785). We now show that herbimycin A induces a profound decrease in the total cellular activity of transmembrane tyrosine kinase receptors, such as insulin-like growth factor, insulin, and epidermal growth factor receptors. A substantial proportion of the in vivo inhibition could be explained by an increase in the rate of degradation. The enhanced degradation of insulin-like growth factor-insulin receptor was prevented by inhibitors of the 20S proteasome, whereas neither lysosomotropic agents nor general serine- and cysteine-protease inhibitors were active in preventing receptor degradation induced by herbimycin A. Moreover, in a temperature-sensitive mutant cell line defective in the E1-catalyzed activation of ubiquitin, herbimycin A treatment at the restrictive temperature did not result in the degradation of insulin receptor. These results suggest that herbimycin A represents a novel class of drug that targets the degradation of tyrosine kinases by the 20S proteasome. The ubiquitin dependence of this process indicates that this degradation of tyrosine kinases might involve the 20S proteasome as the proteolytic core of the ubiquitin-dependent 26S protease.

Amino Acid Sequence↗
PubMed1995

Insulin-like growth factors modulate the growth inhibitory effects of retinoic acid on MCF-7 breast cancer cells.

Retinoids are currently being tested for the treatment and prevention of several human cancers, including breast cancer. However, the anti-cancer and growth inhibitory mechanisms of retinoids are not well understood. All-trans retinoic acid (RA) inhibits the growth of the estrogen receptor-positive (ER+) breast cancer cell line, MCF-7, in a reversible and dose-dependent manner. In contrast, insulin-like growth factors (IGF-I, IGF-II) and insulin are potent stimulators of the proliferation of MCF-7 and several other breast cancer cell lines. Pharmacologic doses of RA (> or = 10(-6) M) completely inhibit IGF-I-stimulated MCF-7 cell growth. Published data suggest that the growth inhibitory action of RA on IGF-stimulated cell growth is linear and dose-dependent, similar to RA inhibition of unstimulated or estradiol-stimulated MCF-7 cell growth. Surprisingly, we have found that IGF-I or insulin-stimulated cell growth is increased to a maximum of 132% and 127%, respectively, by cotreatment with 10(-7) M RA, and that 10(-9) - 10(-7) M RA increase cell proliferation compared to IGF-I or insulin alone. MCF-7 cells that stably overexpress IGF-II are also resistant to the growth inhibitory effects of 10(-9) - 10(-7) M RA. Treatment with the IGF-I receptor blocking antibody, alpha IR-3, restores RA-induced growth inhibition of IGF-I-treated or IGF-II-overexpressing MCF-7 cells, indicating that the IGF-I receptor is mediating these effects. IGFs cannot reverse all RA effects since the altered cell culture morphology of RA-treated cells is similar in growth-inhibited cultures and in IGF-II expressing clones that are resistant to RA-induced growth inhibition. These results indicate that RA action on MCF-7 cells is biphasic in the presence of IGF-I or insulin with 10(-9) - 10(-7) M RA enhancing cell proliferation and > or = 10(-6) M RA causing growth inhibition. As IGF-I and IGF-II ligands are frequently detectable in breast tumor tissues, their potential for modulation of RA effects should be considered when evaluating retinoids for use in in vivo experimental studies and for clinical purposes. Additionally, the therapeutic use of inhibitors of IGF action in combination with RA is suggested by these studies.

Breast Neoplasms↗
PubMed1995

Double-blind randomized study of 1 g versus 2 g intravenous ceftriaxone daily in the therapy of community-acquired infections.

In a multicentre, double-blind, randomized study involving four general hospitals in Israel, the efficacy and safety of ceftriaxone 1 g/day i.v. was compared to that of 2 g/day i.v. in the treatment of moderate to severe community-acquired infections requiring hospitalization. Two hundred and twenty-two patients were enrolled; 112 received intravenous ceftriaxone 1 g/day, and 110 received 2 g/day. The two groups were matched demographically, and their mean APACHE II score (10 points) and mean duration of successful therapy (7 days) were identical. The sites of infection in the 1 g and 2 g groups respectively were lower respiratory tract in 57 versus 51 patients, urinary tract in 31 versus 40 patients, and soft tissue in 24 versus 19 patients. There were no significant differences in clinical outcome between the 1 g and 2 g groups, the outcome being cure in 91% versus 86% of patients, improvement in 3% versus 3% of patients, failure in 3% versus 8% of patients, and relapse in 3% versus 3% of patients. The findings of this study indicate that ceftriaxone 1 g/day is as effective as 2 g/day in the treatment of moderate to severe community-acquired infections. The low-dose form is a more economical means of treating these infections.

Adult↗
PubMed1995

Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin.

Both EGF and insulin, or IGF, stimulate the growth of many cell types by activating receptors that contain tyrosine kinase activities. A monoclonal antibody (mAb 225) against the EGF receptor produced in this laboratory has been shown to competitively inhibit EGF binding and block activation of receptor tyrosine kinase. Here we report that a human colorectal carcinoma cell line, DiFi, which expresses high levels of EGF receptors on plasma membranes, can be induced to undergo G1 cell cycle arrest and programmed cell death (apoptosis) when cultured with mAb 225 at concentrations that saturate EGF receptors. Addition of IGF-1 or high concentrations of insulin can delay apoptosis induced by mAb 225, while the G1 arrest cannot be reversed by either IGF-1 or insulin. Insulin/IGF-1 cannot activate EGF receptor tyrosine kinase that has been inhibited by mAb 225. Moreover, an mAb against the IGF-1 receptor, which has little direct effect on DiFi cell growth, can block the capacity of insulin/IGF-1 to delay apoptosis induced by mAb 225, suggesting that the insulin/IGF-1-mediated delay of apoptosis is acting through the IGF-1 receptor. In contrast, insulin/IGF-1 cannot delay the apoptosis caused by the DNA damaging agent, cisplatin. The results indicate that EGF receptor activation is required both for cell cycle progression and for prevention of apoptosis in DiFi cells, and that a signal transduction pathway shared by receptors for insulin/IGF-1 and EGF may be involved in regulating apoptosis triggered by blockade of the EGF receptor.

Antibodies, Monoclonal↗
PubMed1994

[Merkel cell carcinoma of the eyelid].

Merkel cell carcinoma is an infrequent but highly malignant cutaneous neoplasm. In a 73-year-old woman, a Merkel cell carcinoma of the right upper lid developed within 1 month, recurred within a month after its first removal, and metastasized to the parotid 2 months after secondary excision.

Aged↗
PubMed1994

Patient dissatisfaction after functionally successful conjunctivodacryocystorhinostomy with Jones tube.

Conjunctivodacryocystorhinostomy with a Jones tube is an accepted procedure for the treatment of epiphora resulting from obstructed canaliculi. Because of our clinical impression that a high rate of functional success after surgery is associated with a lower rate of patient satisfaction, we analyzed the results and patient satisfaction of 121 patients who underwent conjunctivodacryocystorhinostomy with Jones tubes. The surgical success rate was 92.6% (112 of 121 patients). However, 13 of 112 patients (11.6%) whose operation was functionally successful were not satisfied and 36 of 112 patients (32%) reported having more complications than expected. The highest rate of dissatisfied patients occurred in patients 70 years of age or older (ten of 46 patients, 22%) and in patients 19 years of age or younger (one of four patients). Thus, the indication for conjunctivodacryocystorhinostomy in these age groups should be limited to exceptionally remarkable symptomatic cases. The drawbacks of the procedure should be explained to all candidates to minimize dissatisfaction resulting from unrealistic expectations.

Adolescent↗
PubMed1994

p53Val135 temperature sensitive mutant suppresses growth of human breast cancer cells.

One common step in the malignant progression of a wide variety of human cancers seems to be inactivation of the p53 gene, via point mutation or deletion or both; or overexpression of mutated protein with dominant transforming activity. This study shows a suppressive effect of wild type p53 on the growth of human breast cancer cells. Introduction of wild type p53 versus mutant into five human breast cancer cell lines containing mutant p53 resulted in a marked reduction in colony formation. Two of these were transfected with human wt p53 expression vectors and the other three were infected with retroviruses packaging human wt p53, both showing similar reduction in the number of surviving colonies, suggesting a role for wt p53 in suppression of breast cancer cell growth. Direct evidence for growth suppression was obtained by introduction of the temperature sensitive p53Val135 into Hs578T human breast cancer cells containing a mutant p53. This murine mutant allele p53Val135 functions as an oncogene at 37 degrees C as a tumor suppressor at 32 degrees C. The cell line generated was strongly growth inhibited at the restrictive temperature (31.5 degrees C), at which temperature the suppressor form is expressed. This inhibition of proliferation was reversible upon a temperature upshift. Analysis of the cell cycle distribution shows these growth suppressed cells to be inhibited in the G1 phase of the cell cycle. Thus wt p53 may have an important role in breast cancer tumorigenesis.

3T3 Cells↗
PubMed1994

Insulin and insulin-like growth factor signaling are defective in the MDA MB-468 human breast cancer cell line.

Polypeptide growth factors including the insulin-like growth factors (IGFs), insulin, and transforming growth factor-alpha are mitogens for many breast cancer cell lines and may act as regulators of cancer cell growth. In a human breast cancer cell line MCF-7, which expresses IGF-I receptor (IGF-IR), stimulation with insulin or IGFs resulted in autophosphorylation of the IGF-IR in an increased proportion of ras bound to GTP and in the association of phosphatidylinositol 3'-kinase (PI3K) activity and of p85-PI3K with M(r) 185,000 phosphotyrosinylated proteins corresponding in size to insulin/IGF-IR substrates. These events were associated with enhanced proliferation. MDA MB-468 is a human breast cancer cell line which expresses insulin receptor and high levels of epidermal growth factor/transforming growth factor alpha receptor but low levels of IGF-IR. In this cell line, insulin stimulated autophosphorylation of IR at physiological concentrations and promoted the association of PI3K activity and of p85 with phosphotyrosine-containing proteins. Insulin did not, however, induce increased ras.GTP, and the cells exhibited minimal proliferation in response to insulin. Unlike insulin treatment, epidermal growth factor stimulation of MDA MB-468 cells is mitogenic and resulted in increased ras.GTP content, suggesting that the failure of insulin to induce these changes is not due to alterations in these signaling molecules. We conclude that there is a postreceptor defect in insulin signaling in MDA MB-468 which prevents the activation of ras and the induction of mitogenesis. Activation of PI3K by insulin is not sufficient to mediate mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

A truncated cyclin D1 gene encodes a stable mRNA in a human breast cancer cell line.

The G1 cyclin D1 is amplified in approximately 20% of human breast cancers and is frequently overexpressed as part of an amplicon in these tumors, suggesting a potential role for this gene in the pathogenesis of breast cancer. Although amplification of cyclin D1 occurs in human breast cancer, it is possible that another gene in the amplicon is the relevant oncogene in these cancers. We now report a truncation of the cyclin D1 gene in a human breast cancer cell line, associated with overexpression of a short cyclin D1 mRNA. In a survey of breast cancer cell lines and tumors by Southern blot hybridization, using a 1.2 kb human cyclin D1 cDNA, we observed that genomic DNA derived from the MDA MB-453 cell line contains an extra band in the Bg1II and BamHI digests, suggesting that one allele of gene is altered. Moreover, the altered allele is amplified three-fold relative to the normal allele, and contains a 3' deletion. On Northern analysis, the MDA MB-453 line has a marked increase in 1.1 to 1.3 kb transcripts, which are truncated at the 3' end, in contrast to the normally predominant 4.2 kb transcript. The 1.1-1.3 kb cyclin D1 mRNA has a longer half-life than the 4.2 kb mRNA, indicating that the 3' truncation may contribute an increased stability and therefore an elevated steady-state level of the short mRNA. These alterations in the cyclin D1 gene and mRNA suggest that altered expression of cyclin D1 may be important in the malignant transformation of this cell line, and support the identification of cyclin D1 as a dominant oncogene at 11q13 in human breast cancer.

Base Sequence↗
PubMed1992

Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression.

It has been proposed that the insulin-like growth factors (IGFs) can act as autocrine and/or paracrine growth promoters in breast cancer. To investigate this hypothesis, we infected early passage MCF-7 cells with a retroviral vector containing the coding sequence for the IGF-II preprohormone along with a constitutive cytomegalovirus promoter sequence. These cells do not normally express IGF-I or IGF-II. After infection with the retroviral vector, several single cell clones were analyzed. Seven of nine isolated clones expressed very high levels of IGF-II mRNA. Biologically active IGF-II protein was easily detectable in the medium conditioned by the IGF-II-expressing clones, and IGF receptors were down-regulated in these. All IGF-II-expressing clones showed marked morphological changes in anchorage-dependent culture, growing in large clumps and as free-floating colonies. The cells also cloned in soft agar in the absence of estrogen, while the wild-type MCF-7 cells and control cells infected with an irrelevant DNA sequence showed none of these properties. alpha IR-3, an antibody that blocks the type I IGF receptor, inhibited the growth of IGF-II-expressing clones in serum-free medium. This model demonstrates that IGF-II can serve as an autocrine growth stimulant in breast cancer epithelial cells and that IGF-II overexpression may be capable of mediating malignant progression in human breast cancer.

Breast Neoplasms↗
PubMed1991

Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions.

Breast tumors are a complex mix of epithelial, stromal, and vascular elements. We examined primary cultures of breast fibroblasts derived from benign and malignant lesions for expression of various growth factors. All fibroblast cultures, regardless of whether they were derived from benign or malignant lesions, expressed platelet-derived growth factor A chain, basic fibroblast growth factor, fibroblast growth factor 5, and transforming growth factor beta 1 mRNA. None expressed platelet-derived growth factor B chain or transforming growth factor alpha mRNA. However, examination of mRNA expression for the insulin-like growth factors revealed that 7 of 8 fibroblasts derived from benign lesions expressed insulin-like growth factor I (IGF-I) mRNA, while only 1 of 9 fibroblasts derived from malignancies expressed IGF-I mRNA. The opposite picture was seen for insulin-like growth factor II (IGF-II) mRNA expression, in which 1 of 9 benign-derived fibroblasts expressed IGF-II mRNA, while 5 of 9 malignant-derived fibroblasts expressed IGF-II. This correlated with previous in situ hybridization data, which showed IGF-I mRNA expression confined to the stroma of benign breast tissue. PDGF treatment of tumor fibroblasts resulted in a 3-fold increase in IGF-II mRNA. Thus there was an apparent dichotomy between IGF-I mRNA expression in the majority of fibroblasts derived from benign lesions and IGF-II mRNA expression in the majority of tumor-derived fibroblasts. Since the insulin-like growth factors are potent mitogens for breast tumor epithelial cells, this further supports the notion of a paracrine growth-promoting role for the insulin-like growth factors in breast lesions and suggests that IGF-II may be the more important growth promoter in malignant lesions.

Breast Diseases↗