Biomedical subjects

Adil Daud

Publications and source records attributed to Adil Daud.

9 recordsLinked to original sources

PubMed2007

The Src signaling pathway: a potential target in melanoma and other malignancies.

Although Src was the first oncogene to be discovered as the transforming protein of the Rous sarcoma virus almost three decades ago, the role of Src and the Src family kinases in human oncogenesis is still not completely understood. Recent studies have shown that Src regulates cell adhesion, invasiveness and motility in cancer cells and in tumor vasculature, rather than directly influencing cell replication. The role of the Src family kinases in human cancer is evolving and elevated levels of Src kinase activity have been reported in a number of human cancers in vitro and in vivo. Src expression and activity are increased in melanoma cell lines and in melanoma tumors in vivo. Src can activate STAT3, STAT5 and other downstream targets in melanoma. Src and STAT3 are expressed in their activated forms in both primary and metastatic melanoma in humans, although the expression level is variable. Cumulatively, these data mark Src signaling as attractive therapeutic targets in melanoma. Studies are currently underway with novel Src inhibitors in melanoma and in other tumor types.

Animals↗

PubMed2006

Down-regulation of pro-apoptotic genes is an early event in the progression of malignant melanoma.

INTRODUCTION: Down-regulation of apoptosis genes has been implicated in the development and progression of malignant melanoma. We used cDNA microarray to evaluate pro-apoptotic gene expression comparing normal skin to melanoma (thin and thick), nodal disease and distant metastases. METHODS: Twenty-eight specimens including skin (n = 1), thin melanoma (n = 6), thick melanoma (n = 7), nodal disease (n = 6), and distant metastases (n = 8), were harvested at the time of resection from 16 individuals. RNA was isolated and microarray analysis utilizing the Affymetrix GeneChip (54,000 genetic elements, U133A+B... levels) was performed. Mean level of expression was calculated for each gene within a sample group. Expression profiles were then compared between tissue groups. Student's t-test was used to determine variance in expression between groups. RESULTS: We reviewed the expression of 54,000 genetic elements, of which 2,015 were found to have significantly altered expression. This represents 1,602 genes. Twenty-two pro-apoptotic genes were found to be down-regulated when compared to normal skin. Overall reduction was evaluated comparing normal skin to metastases with a range of 3.31-64.04-fold-decrease. When comparing the tissue types sequentially, the greatest fold-decrease in gene expression occurred when comparing skin to all melanomas (thin and thick) (p = 0.011). Subset analysis comparing normal skin to thin melanoma or thick melanoma, revealed the greatest component of overall reduction at the transition from thin to thick lesions (p = 0.003). CONCLUSION: Sequential down-regulation of pro-apoptotic genes is associated with the progression of malignant melanoma. The greatest fold-decrease occurs in the transformation from thin to thick lesions.

Apoptosis↗

PubMed2006

Increased bioavailability of intravenous versus oral CI-1033, a pan erbB tyrosine kinase inhibitor: results of a phase I pharmacokinetic study.

PURPOSE: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability. EXPERIMENTAL DESIGN: Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis. RESULTS: Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen. CONCLUSIONS: CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.

Administration, Oral↗

PubMed2006

Evaluation of toxicity following electrically mediated interleukin-12 gene delivery in a B16 mouse melanoma model.

PURPOSE: Interleukin-12 (IL-12) has potential as an immunotherapeutic agent for the treatment of cancer but is unfortunately associated with toxicity. Delivery of a plasmid encoding IL-12 with electroporation induces an antitumor effect in the B16 mouse melanoma model without serious side effects. To translate this observation to the clinic, an evaluation of toxicity was done in the mouse model. EXPERIMENTAL DESIGN: Weight change, tumor response, blood chemistry and hematology values, and serum IL-12 levels were evaluated. Multiple tissues were analyzed histopathologically. RESULTS: A pronounced reduction in tumor volume, including a large percentage of complete regressions, was observed after electrically mediated gene therapy. No significant increases in serum IL-12 levels were detected. Tumor-bearing mice showed an increased number of atypical hematology values when compared with normal naive controls. Statistically significant differences in chemistry and hematology values were observed sporadically in most of the standard chemistry and hematology categories in all groups. The only histopathologic abnormality specific to the animals receiving both plasmid and electroporation was inflammation associated with the kidney at the last time point. CONCLUSIONS: In general, mice that received both plasmid and electroporation showed the least abnormal histopathologic findings and were found to be in the best health, reflecting the reduced burden of disease. No significant toxic effects due to the IL-12 gene therapy were observed.

Animals↗

PubMed2006

Melanoma.

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Algorithms↗

PubMed2005

Phase II trial of karenitecin in patients with malignant melanoma: clinical and translational study.

PURPOSE: A phase II trial of the novel camptothecin karenitecin (BNP1350) was conducted to determine its efficacy and tolerability in patients with metastatic melanoma. Patients were biopsied to determine topoisomerase expression at baseline and response to therapy. PATIENTS AND METHODS: Eligible patients had metastatic melanoma with up to three prior chemotherapy and/or any number of immunotherapy regimens. Treatment consisted of an i.v. infusion of 1 mg/m(2) karenitecin daily for 5 days with cycles repeated every 3 weeks. Fine-needle aspiration biopsies were done before treatment and on day 3 to determine topoisomerase expression from patients' tumors. RESULTS: Forty-three patients were evaluable for response and toxicity. Most patients (72%) had stage M1C disease and were previously exposed to chemotherapy (56%). The investigational agent was well tolerated with limited gastrointestinal side effects or fatigue. The major toxicity seen was reversible noncumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were seen, but 33% of the patients had disease stabilization lasting > or =3 months. Topoisomerase I, IIalpha, and IIbeta expression and localization were determined in a subset of patients. Topoisomerase I expression was highest, followed by topoisomerase IIbeta and topoisomerase IIalpha. CONCLUSION: Karenitecin was a well-tolerated investigational agent in this phase II study; side effects were generally mild and mostly hematologic. Karenitecin has significant activity in metastatic melanoma. Melanoma metastases express high levels of topoisomerase I. We did not observe any compensatory increase in topoisomerase II upon treatment with karenitecin.

Adult↗

PubMed2005

Cutaneous melanoma: prognostic factors.

BACKGROUND: Recent data have changed our views of prognostic factors in cutaneous melanoma. While some newer methods have yielded better prognostic information, some insights have evolved as a result of large-scale population-based analyses. METHODS: We review current data on several different prognostic factors and divide these factors according to their application in localized primary melanoma or metastatic melanoma. For each prognostic factor, the level of evidence supporting its use and its applicability to clinical practice are considered. RESULTS: For localized primary melanoma, the dominant predictors of survival include lesion thickness, ulceration, and lymph node involvement. Factors such as age, sex, anatomic location, and satellite/in-transit lesions are important in localized melanoma. Factors currently being investigated are tumor vascularity, vascular invasion, mitotic rate, tumor regression, and tumor-infiltrating lymphocytes. For metastatic melanoma, the most important prognostic factors are site of metastases and the presence of elevated serum lactic dehydrogenase. The value of these prognostic factors to clinicians caring for melanoma patients is discussed. CONCLUSIONS: A better understanding of prognostic factors in cutaneous melanoma has evolved over the last decade, allowing oncologists to provide appropriate treatment for their patients. Many of the prognostic factors are interrelated. In the near future, it is expected that several molecular genetic factors will provide more insight into the prognosis of patients with melanoma.

Humans↗

PubMed2002

Roles of activated Src and Stat3 signaling in melanoma tumor cell growth.

Activation of protein tyrosine kinases is prevalent in human cancers and previous studies have demonstrated that Stat3 signaling is a point of convergence for many of these tyrosine kinases. Moreover, a critical role for constitutive activation of Stat3 in tumor cell proliferation and survival has been established in diverse cancers. However, the oncogenic signaling pathways in melanoma cells remain to be fully defined. In this study, we demonstrate that Stat3 is constitutively activated in a majority of human melanoma cell lines and tumor specimens examined. Blocking Src tyrosine kinase activity, but not EGF receptor or JAK family kinases, leads to inhibition of Stat3 signaling in melanoma cell lines. Consistent with a role of Src in the pathogenesis of melanoma, we show that c-Src tyrosine kinase is activated in melanoma cell lines. Significantly, melanoma cells undergo apoptosis when either Src kinase activity or Stat3 signaling is inhibited. Blockade of Src or Stat3 is also accompanied by down-regulation of expression of the anti-apoptotic genes, Bcl-x(L) and Mcl-1. These findings demonstrate that Src-activated Stat3 signaling is important for the growth and survival of melanoma tumor cells.

Apoptosis↗

PubMed2002

A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies.

PURPOSE: The purpose of this study was to evaluate the toxicity and pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as a twice weekly i.v. bolus for 2 weeks, followed by a 1-week recovery period in patients with advanced solid tumor malignancies. EXPERIMENTAL DESIGN: In this Phase I trial, 43 patients were treated with PS341 in doses ranging from 0.13 to 1.56 mg/m2/dose. A standard Phase I design was used. Pharmacodynamic studies were performed to access 20S proteasome activity. RESULTS: Forty-three patients were treated with 89 cycles of PS341. Patients were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. A dose-related inhibition of 20S proteasome activity with increasing dose of PS341 was seen. There was one major response in a patient with refractory non-small cell lung carcinoma. CONCLUSIONS: Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted.

Adult↗