Chris Theodossiou

Clinical Protocol The Treatment of Malignant Mesothelioma with a Gene Modified Cancer Cell Line: A Phase I Study

1.1 To evaluate the safety and side effects of treatment with the gene-modified ovarian cancer cell line PA1-STK, which is administered intrapleurally and activated with ganciclovir. 1.2 To determine a maximum treatment dose (MTD) and the dose limiting side effects of this treatment. 1.3 To evaluate the immunologic response to this treatment. 1.4 To measure intrapleural pharmakokinetics of the drug ganciclovir. 1.5 To observe for clinical effects on the residual malignant mesothelioma.

Propylthiouracil reduces xenograft tumor growth in an athymic nude mouse prostate cancer model

METHODS Several anecdotal reports indicate that cancer may occasionally remain in a dormant state for prolonged periods in patients with hypothyroidism. Once the hypothyroid state is recognized and supplementation therapy with thyroid hormones is initiated, disease progression occurs. In this experiment, 6-n-propyl-2-thiouracil (PTU) was added to the water of athymic nude mice. The animals were subsequently inoculated with cells from a human prostate cancer cell line. RESULTS The growth rate of subcutaneously implanted prostate xenografts was significantly slower in mice treated with PTU compared with mice that did not receive PTU. In a separate experiment, tritiated thymidine incorporation assays were performed in DU145 and PC3 human prostate cancer cells with and without PTU. No significant differences were observed, indicating that PTU did not exert any antitumor effect in vitro. CONCLUSIONS Our study demonstrates that PTU inhibits the growth of human prostate tumors in nude mice via an indirect effect. This antitumor effect may be caused by hypothyroidism. This is the first in vivo study suggesting potential therapeutic applications for thyroid hormone manipulations in human cancer of the prostate. Further studies will determine growth kinetics of xenotransplanted prostate cancer in vitro and in vivo. PTU-induced hypothyroidism may be further explored in conjunction with other antineoplastic therapy.

Poly-l-lysine-Based Molecular Conjugate Vectors: A High Efficiency Gene Transfer System for Human Progenitor and Leukemia Cells

Background:Targeted, specific receptor mediated gene transfer is a major goal of gene therapy research to accomplish gene transfer exclusively to the desired cell population. Methods:First, the use of natural receptor for stem cell factor and transferrin receptor-targeted gene transfer using poly-l-lysine–based molecular conjugate vectors was evaluated in a panel of hematopoietic progenitor cell lines. Second, the ability of poly-l-lysine to enhance adenovirus mediated gene transfer efficiency was examined in different cell lines by using recombinant adenovirus-poly-l-lysine molecular conjugate conglomerates (recMCVEGFP). Results:Despite effective ligand internalization receptor, gene expression amplification in receptor positive cell lines was not uniformly observed. Therefore, using a poly-l-lysine–based, receptor-targeted vector, neither transferrin nor natural receptor for stem cell factor mediated gene transfer can be considered a universally applicable procedure that exclusively depends on the presence of receptors on the cell surface; rather, it is a cell specific phenomenon. In our model, poly-l-lysine is the major contributor for gene transfer to hematopoietic progenitor cells, mediating the initial vector-cell binding. Human progenitor cell lines are poorly transduceable with recombinant adenovirus vectors. This new poly-l-lysine–modified, adenovirus-based vector could overcome virus tropism restrictions and consistently achieve very high transduction efficiency (>90%) in cells otherwise refractory to adenovirus gene transfer. Conclusions:Polylysine-based adenovirus vectors may have promise for situations in which high-efficiency gene transfer with transient high level transgene expression in hematopoietic cells is needed, such as leukemia vaccine protocols or for purging strategies in leukemia cell contaminated stem cell preparations.

Efficient c-kit Receptor-Targeted Gene Transfer to Primary Human CD34-Selected Hematopoietic Stem Cells

ABSTRACT We have previously reported effective gene transfer with a targeted molecular conjugate adenovirus vector through the c-kit receptor in hematopoietic progenitor cell lines. However, a c-kit-targeted recombinant retroviral vector failed to transduce cells, indicating the existence of significant differences for c-kit target gene transfer between these two viruses. Here we demonstrate that conjugation of an adenovirus to a c-kit-retargeted retrovirus vector enables retroviral transduction. This finding suggests the requirement of endosomalysis for successful c-kit-targeted gene transfer. Furthermore, we show efficient gene transfer to, and high transgene expression (66%) in, CD34-selected, c-kit+ human peripheral blood stem cells using a c-kit-targeted adenovirus vector. These findings may have important implications for future vector development in c-kit-targeted stem cell gene transfer.

Dose escalation of docetaxel concomitant with hypofractionated, once weekly chest radiotherapy for non-small-cell lung cancer: a phase I study.

Hypofractionated chest radiotherapy has been used as an alternative when standard fractionated schedules are neither practical nor feasible. To explore docetaxel as radiosensitizer in a hypofractionated chest irradiation schedule, a docetaxel dose escalation study was conducted in which 26 patients with advanced non-small-cell lung cancer (NSCLC) (stages III and IV) were enrolled. Docetaxel was administered 24 hours prior to irradiation (starting dose 10mg/m2; escalating in 5mg/m2 increments). Radiation was administered at 500 cGy (one fraction) once/wk for 10 consecutive weeks (5000 cGy total). The docetaxel dose was escalated up to 45 mg/m2/wk. The treatment was well tolerated over 10 consecutive weeks without requiring dose reductions or interruptions. Toxicities were mainly docetaxel related. One of 19 evaluable patients had a complete radiographic response within the radiation treatment port, 13 had a partial response, and 5 had stable disease. No patient recurred within the radiation field. Three patients who underwent surgical resection following treatment were pathologically down staged to stage I. This trial of a small group of patients supports, in selected patients, synchronous administration of effective hypofractionated, radiosensitized radiation therapy and optimized systemic chemotherapy.

Treatment of Thrombotic Thrombocytopenic Purpura with the Cryosupernatant Fraction of Plasma: A Case Report and Review of the Literature

We report a case of thrombotic thrombocytopenic purpura (TTP) that did not respond to extensive plasma exchange with fresh frozen plasma (FFP) but responded to plasma exchange with cryosupernatant. Several reports indicate that responses to cryosupernatant may be seen in patients refractory to FFP, and this approach may be appropriate in these patients before one recommends a splenectomy. The literature on refractory TTP treated with cryosupernatant exchange is reviewed.

Non-Hodgkin's lymphomas.

Lymphomas are a heterogeneous group of malignancies that originate in the lymphatic organs. Many of them express either B-cell or T-cell markers, or both, indicating disruption of normal development at a precursor stage. Approximately 4% of cancers in the United States are non-Hodgkin’s lymphomas (NHL), and the lifetime risk of NHL is 2.08%. It is estimated that 54,900 new cases of NHL were diagnosed in the United States and 26,100 patients died of the disease in 2000. NHL accounts for 5% of cancer-related deaths and is the leading cause of cancer-related death for people between 20 and 40 years of age. NHL is slightly more common in men, with an incidence of 19.2 per 100,000 compared with 12.2 per 100,000 for women. The incidence rate for whites is 15.9 per 100,000 compared with 12.0 per 100,000 for African Americans. The median age at diagnosis is 65 years; the incidence increases with age and peaks in the 80-to-85-year age group. The incidence of NHL has been steadily increasing for the past 50 years. The largest increases have occurred in patients with high-grade lymphomas. The incidence of extranodal lymphomas has increased more rapidly than nodal disease, whereas the incidence of primary central nervous system (CNS) lymphoma in the United States increased more than tenfold between 1973 and 1992. This increase is in part due to the AIDS epidemic, although the incidence of CNS lymphoma has increased in non-AIDS populations as well. The observed increase in incidence of NHL is most likely multifactorial. Many investigators suspect that it may be due to the increased exposure to toxic substances and carcinogens. However, at least part of the rise in incidence can be explained by the aging population and the AIDS epidemic. In addition, increased ability to diagnose the disease through improved imaging studies and new molecular biologic techniques such as polymerase chain reaction (PCR) and gene rearrangement has also contributed to the rise in its incidence through detection of previously undiagnosed disease. Finally, the current classification system may also partially contribute to the increase. Cases that were previously classified as atypical Correspondence: Chris Theodossiou, MD, Department of Medicine, Division of Hematology-Oncology, Louisiana State University School of Medicine, 1542 Tulane Avenue, Room 604K, New Orleans, LA 70112. E-mail: ctheod@lsuhsc.edu PROD. # GRF20304

Plasmacytoma in HIV Disease: Two Case Reports and Review of the Literature

Two cases of plasmacytoma in the setting of human immunodeficiency virus infection are presented. The currently available literature is reviewed.