Drug development in prostate cancer.

Despite strategies aimed at early detection and treatment, prostate cancer remains a leading cause of morbidity and mortality among males. Current therapies have limited impact on the natural history of metastatic hormone-refractory prostate cancer (HRPC). With an improved understanding of tumor biology, including apoptosis, differentiation, cell cycling and signaling, and angiogenesis, many potential new targets for therapy have been unveiled.

Post-transplant immunotherapy designed to prevent cancer recurrence.

Most stem cell transplants are performed to treat neoplasms. Yet many patients survive the transplant but die from cancer recurrence post-transplant. The incorporation of post-transplant immunotherapy offers the potential for enhanced antitumor efficacy.

Metastatic breast cancer.

The unfortunate reality of metastatic breast cancer is that all treatment is palliative in nature. This is a disease that currently has no cure and for which therapy is directed towards accentuating survival and relieving symptoms. Current technology allows the prediction and detection of metastases earlier and with greater accuracy.

Phase I trial of intravenous thymidine and carboplatin in patients with advanced cancer.

Purpose: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m(2) in a phase I trial.

Patients And Methods: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone.

Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812).

Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4-128 mg/m2.

In vivo gammadelta T cell priming to mycobacterial antigens by primary Mycobacterium tuberculosis infection and exposure to nonpeptidic ligands.

Background: The recognition of phosphorylated nonpeptidic microbial metabolites by Vgamma9Vdelta2 T cells does not appear to require the presence of MHC molecules or antigen processing, permitting rapid responses against microbial pathogens. These may constitute an important area of natural anti-infectious immunity. To provide evidence of their involvement in immune reactivities against mycobacteria, we measured the responsiveness of peripheral blood Vgamma9Vdelta2 T cells in children with primary Mycobacterium tuberculosis (MTB) infections.

High dose rate brachytherapy in the treatment of cervical carcinoma.

Intracavitary brachytherapy has been shown to significantly reduce the rate of local recurrence in patients with cervix carcinoma. High dose rate (HDR) techniques use a high-intensity source to deliver high total doses of radiation over minutes, leading to the development of out-patient use of HDR brachytherapy procedures. HDR fractionation protocols that demonstrate rates of local control that are equivalent to low dose rate techniques and use smaller dose per fraction are recommended to decrease the probability of long-term complications with HDR.

GD3 ganglioside antibody augments tumoricidal capacity of canine blood mononuclear cells by induction of interleukin 12.

Monoclonal antibody R24 recognizes ganglioside GD3 expressed on the cell surfaces of some tumor cells and on a subset of human T lymphocytes. Binding of R24 to these lymphocytes induces proliferation, cytokine production, and activation of intracellular signaling pathways. In the current report, we investigated expression of gangliosides by canine mononuclear immune cells and studied the ability of antiganglioside antibody to activate these cells using tumor cell killing as a measure of activation.

p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells.

The cell cycle regulatory genes p16/CDKN2 and RB are frequently deleted in prostate cancers. In this study, we examined the role of alterations in p16 and pRb during growth, senescence, and immortalization in vitro of human prostate epithelial cells (HPECs). HPECs are established from normal prostate tissues and cultured on collagen-coated dishes.

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.

Purpose: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min.

Patients And Methods: Nine patients with refractory cancer were treated from October 1995 to June 1997.

Current initial therapy of stage III and IV ovarian cancer: challenges for managed care.

Patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III or stage IV) have improved their long-term prognosis, but the majority will still die of their disease. The current standard therapy, which involves aggressive cytoreductive surgery (removal of all visible tumor) followed by platinum/paclitaxel chemotherapy, has increased 5-year survival rates considerably over the last three decades. The choice of treatment for patients with stage III or IV disease in the managed care setting must consider survival rates, patient quality of life, and cost-effectiveness.

Drug development in solid tumors: personal perspective of Dr. Emil J Freireich's contributions.

The development of chemotherapy for patients with the major cancers progressed from the initial success attained in the treatment of acute leukemias and choriocarcinoma. Many of the principles of therapy were based on the concepts developed in the experimental laboratories and early clinical studies done at the NIH Clinical Center and other centers around the country. The purpose of this review is to describe some of the early advances in cancer therapy and show how many are based on the efforts of Dr.

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis.

We targeted expression of human/fly chimeric Bcr-Abl proteins to the developing central nervous system (CNS) and eye imaginal disc of Drosophila melanogaster. Neural expression of human/fly chimeric P210 Bcr-Abl or P185 Bcr-Abl rescued abl mutant flies from pupal lethality, indicating that P210 and P185 Bcr-Abl can substitute functionally for Drosophila Abl during axonogenesis. However, increased levels of neurally expressed P210 or P185 Bcr-Abl but not Drosophila Abl produced CNS defects and lethality.

Efficacy of suramin against human prostate carcinoma DU145 xenografts in nude mice.

Purpose: Toward developing a model to study the mechanism of action of suramin against prostate cancer, we identified the effect of suramin on the growth of xenografts of the androgen-independent human prostate carcinoma DU145 cell line and our subline of suramin-resistant (SR) DU145 cells which are less responsive to suramin in vitro.

Methods: Athymic nude mice bearing DU145 or SR DU145 xenografts were treated intraperitoneally (IP) once weekly with normal saline (vehicle control) or suramin in normal saline. For data analysis mice were grouped as follows: 0 mg/kg (controls), < 210 mg/kg, 210 to 260 mg/kg, or >260 mg/kg suramin.

Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells.

Androgen-independent metastatic prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. In this study, we evaluate DNA hypermethylation as a potential transcriptional regulatory mechanism in AR-negative prostate cancer cell lines. Nucleotide sequence analysis demonstrates an approximately 15-kb CpG island in the AR gene that encompasses the transcription start site and exon 1.

The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women.

Background: Calcium and vitamin D have been hypothesized to reduce colorectal cancer risk. Epidemiological evidence, however, is mixed.

Methods: To explore those relationships, data were collected as part of a population-based, case-control study of colorectal cancer in Wisconsin women (678 controls, 348 colon and 164 rectal cancer cases).

Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.

Transcription factor activation in lymphokine activated killer cells and lymphocytes from patients receiving IL-2 immunotherapy.

Administration of the cytokine interleukin-2 (IL-2) can result in therapeutic benefits for individuals with renal cell carcinoma and melanoma. Here we report an analysis of the transcription factor families AP-1, Sp1, NF-kappaB, and signal transducers and activators of transcription (STAT) in cancer patients' lymphocytes before and after IL-2 immunotherapy, as assessed by a gel-shift assay. An in vitro surrogate of IL-2 immunotherapy is the incubation of fresh peripheral blood mononuclear cells (PBMC) from healthy individuals in IL-2 for several days, resulting in the production of lymphokine-activated killer (LAK) activity in these cultures.

Diabetes, body size, and risk of endometrial cancer.

Data from a population-based case-control study of Wisconsin women were used to evaluate the relation of diabetes to the risk of endometrial cancer on the basis of body mass index (BMI). Cases (n=723) were identified from a statewide tumor registry; controls (n=2,291) were selected randomly from population lists. Diabetes status, weight, height, and other factors were ascertained by telephone interview.

L-S,R-buthionine sulfoximine: historical development and clinical issues.

L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines.

Methotrexate resistance in human uroepithelial cells with p53 alterations.

Purpose: Bladder cancers are frequently treated with combination chemotherapy that includes methotrexate (MTX). The development of drug resistance is a common problem in treatment of bladder cancers. We tested if the status of p53 and/or pRb affects the development of MTX resistance in bladder epithelial cell lines.

Usual consumption of plant foods containing phytoestrogens and sex hormone levels in postmenopausal women in Wisconsin.

Consumption of phytoestrogens may reduce hormone-dependent cancer risk through alterations in the actions or metabolism of steroid hormones. Studies in humans of phytoestrogen-hormone interactions have been limited and inconsistent. Relations between the consumption of phytoestrogen-containing foods and serum sex hormones and sex hormone-binding globulin were studied in a population-based sample of postmenopausal women who participated in the Nutritional Factors in Eye Disease Study of the Beaver Dam Eye Study.

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin.

Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements.