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Barbara Jacobs

Publications and source records attributed to Barbara Jacobs.

7 recordsLinked to original sources
PubMed2006

Short communication: phase I clinical and gene modulatory evaluation of tamoxifen and IFN-alpha2b.

Preclinical studies had determined that tamoxifen and interferon-alpha2b (IFN-alpha2b) synergistically inhibited growth of both estrogen-receptor positive and negative murine tumor xenografts and had combined antiangiogenic effects and that tamoxifen potentiated IFN-stimulated gene (ISG) expression. A phase I trial in 26 patients was conducted using the combination to define tolerance and potentiation of ISG expression. IFN- alpha2b at a dose of 3 x 10(6) units/m(2) daily was given subcutaneously (s.c.), and tamoxifen was initiated as a loading dose of 150 mg/m(2) and then 60 mg/m(2) twice daily on day 8. At this initial dose, reduction of dose of IFN- alpha2b was required in 4 of 11 patients, primarily because of fatigue. Another group of patients was treated with an identical tamoxifen dose but with IFN-alpha2b reduced to 2 x 10(6)/m(2) U; this was better tolerated. As the projected serum tamoxifen level to reduplicate preclinical effects was 300 mg/m(2), dose escalation in a third cohort was undertaken; it had to be discontinued secondary to grade III or IV toxicity in 2 of 2 patients. Increases in products of transcriptionally regulated ISGs, beta (2)-microglobulin, neopterin, and ISG15 were assessed. All ISGs increased after IFN-alpha2b, but only ISG15 had a further significant rise after initiation of tamoxifen. Because at doses not limited by unacceptable toxicities, no marked potentiation of ISGs by tamoxifen could be identified, clinical evaluation of the combination was terminated.

Angiogenesis Inhibitors↗
PubMed2004

Phase 2 trial of interferon-beta as second-line treatment of ovarian cancer, fallopian tube cancer, or primary carcinoma of the peritoneum.

OBJECTIVE: The protocol was designed to examine the biological effects and clinical activity of interferon-beta in patients with platinum/taxane-resistant ovarian cancer. METHODS: Patients with resistant ovarian and fallopian tube cancers and primary peritoneal carcinoma were treated with recombinant human interferon-beta (Rebif, Serono International) at doses ranging from 6 to 24 million international units (MIU)/day, based on their tolerance to therapy. Levels of IP-10, an interferon-inducible protein, were measured in the serum to evaluate the biological effects of the drug. Also, the peripheral blood mononuclear cells and serum were examined for the induction of previously described novel regulators of interferon-induced death. RESULTS: Eighteen patients were treated, of whom 9 (50%) could be treated at the highest dose level (24 MIU). The major toxicities were fever, chills and fatigue. The median duration of therapy was 6 weeks (range 1-22). No objective responses were observed. IP-10 levels were significantly increased, compared with baseline, at 2, 4, and 6 weeks after initiation of therapy (p < 0.01). CONCLUSIONS: Recombinant human interferon-beta produced a definite biological effect in the serum of treated patients, but this outcome was not translated into any clinically observable or meaningful impact on the disease process.

Aged↗
PubMed2003

Novel growth and death related interferon-stimulated genes (ISGs) in melanoma: greater potency of IFN-beta compared with IFN-alpha2.

Interferon (IFN)-dependent cellular effects are mediated by transcriptional induction of responsive genes, collectively referred to as IFN-stimulated genes (ISGs). Which ISGs regulate the potent antiviral, antiproliferative, apoptosis-inducing, antiangiogenic, and immunologic effects of IFNs remains largely undetermined. To identify genes that might be useful for predicting or targeting apoptosis induction in response to IFNs, WM9 melanoma cells were assessed. WM9 cells had equivalent antiviral activity in response to IFN-beta and IFN-alpha2 but underwent apoptosis only in response to IFN-beta. RNA samples from WM9 cells and WM35 cells, a second melanoma cell line, treated with IFN-alpha2 or IFN-beta were assessed on oligonucleotide arrays. For 95% of genes assessed, IFN-beta was more potent than IFN-alpha2 in inducing ISG expression. Using a 22,000-gene oligonucleotide array, the largest yet reported for assessing ISG induction, approximately 910 genes were identified as induced by IFN-beta at 500 U/ml, and 260 ISGs were identified as significantly induced by IFN-beta at both 50 and 500 U/ml. Of these 260, 209 were defined as new ISGs based on the array analysis. Confirmation by Northern blot or semiquantitative or quantitative PCR was undertaken for 28, and all were confirmed. Nearly half of the 260 genes were functionally categorized as encoding growth-regulatory proteins. Of the 104 with described growth-regulatory function, 71 were induced more than three times by 500 U/ml and twice by 50 U/ml IFN-beta, and 48 of these were new ISGs. Included in this latter category were tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), XIAP-associated factor 1 (XAF1), galectin 9, a cyclin E binding protein, amphiphysin 1, MyD88, and several ubiquitin pathway genes. The diversity of stimulated genes suggests the full therapeutic potential of IFN regulation of gene expression has yet to be realized.

Apoptosis↗
PubMed2002

Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells.

The immunobiology of tumor-infiltrating dendritic cells (DCs) can be strongly influenced by the cytokine environment present in the malignant tissue. We have previously identified discrete melanoma lines, inducing E-cadherin expression on monocyte-derived DCs in vitro. We demonstrate here that this effect, independent of cell contact, is not inducible in the presence of tumor lysates and requires the constitutive expression of IFN stimulated gene 15 (ISG15) by malignant cells. High-density oligonucleotide arrays were used to investigate the expression pattern of 7000 genes in RNA from two melanoma cell clones competent for E-cadherin induction and two clones devoid of DC-modulating capacity. A total of 13 genes encoding soluble proteins were expressed at higher magnitude in melanomas able to induce E-cadherin expression on DCs. Combining those data with quantitative protein assays, we could narrow our investigation down to three factors: the chemokine CCL5 and the cytokines ISG15 and type I IFNs. Strikingly, >7 ng/ml of ISG15 could be detected in the corresponding melanoma-conditioned medium and induction of E-cadherin on DCs failed in the presence of antibodies neutralizing ISG15 protein. Most importantly, strong cytoplasmic expression of ISG15 was detected by immunohistochemistry in the original tumor specimen from which the melanoma cell lines under investigation were derived. These data describe a novel property of ISG15 targeting induction of E-cadherin on DCs and possibly influencing their migratory behavior.

Antibodies↗