Leucovorin modulation of 5-iododeoxyuridine radiosensitization: a phase I study.

Evidence for clinically significant radiosensitization by the halogenated pyrimidine 5-iododeoxyuridine (IdUrd) continues to accumulate. In vitro radiosensitization has been demonstrated in human colon tumor cell lines following exposure to 1-10 micrometer. Coadministration of leucovorin (LV) increases radiosensitization, which correlates directly with increased IdUrd DNA incorporation.

Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: a phase IB study.

Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-four patients with incurable cancers received 2.

Use of a DNA microfluorometric assay to measure proliferative response of mink lung cells to purified TGF beta and to TGF beta activity found in prostate cell conditioned medium.

The proliferative response of Mv1Lu cells to purified TGF beta 1, or TGF beta-like activity released by various cells into medium conditioned over a 24-h period was quantitated by adapting a rapid DNA fluorometric assay. Acid activation of the conditioned medium allowed the amount of biologically latent versus active TGF beta to be quantitated. A neutralizing antibody specific for TGF beta 1, 1.

Alteration of glyceraldehyde-3-phosphate dehydrogenase activity and messenger RNA content by androgen in human prostate carcinoma cells.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.

Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response.

beta-Lapachone and certain of its derivatives directly bind and inhibit topoisomerase I (Topo I) DNA unwinding activity and form DNA-Topo I complexes, which are not resolvable by SDS-K+ assays. We show that beta-lapachone can induce apoptosis in certain cells, such as in human promyelocytic leukemia (HL-60) and human prostate cancer (DU-145, PC-3, and LNCaP) cells, as also described by Li et al. (Cancer Res.

Penile Merkel cell carcinoma.

Merkel cell carcinoma of the genitalia is very rare and to date has been found only in vulvar mucosa. We describe an aggressive Merkel cell tumor in the frenulum of the penis with lymph node metastases, local recurrence, and eventually widespread dissemination. The primary tumor was associated with discontiguous squamous cell carcinoma in situ.

Endocrine control of prostate cancer.

Steroid hormones play an important part in prostate biology. Androgens are crucial for the normal development of the prostate gland and in maintaining its functional state in the adult. It seems that the prolonged presence of androgens might also be an important factor in the development of prostate cancer.

Suramin-induced weakness from hypophosphatemia and mitochondrial myopathy. Association of suramin with mitochondrial toxicity in humans.

Background: Suramin is an antiparasitic drug being evaluated as an antitumor compound. Suramin therapy commonly causes weakness and is known to cause neuropathy. Two potential causes of suramin-induced muscular weakness are described.

Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an attempt at modulation of glutathione.

Purpose: A phase I dose-escalation trial of intravenous (IV) L-buthionine-SR-sulfoximine (BSO) with melphalan (L-PAM) was performed to determine the toxicity and biologic activity of BSO, administered as a short infusion every 12 hours, and the combination of BSO plus L-PAM.

Patients And Methods: Twenty-eight patients with refractory malignancies received 30-minute infusions of BSO every 12 hours for 6 to 10 doses in week 1 followed in week 2 by either IV L-PAM (15 mg/m2) alone or BSO as in week 1 with L-PAM. Patients received the combination in week 5 (course no.

A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma.

Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine.

Taxol in advanced, hormone-refractory carcinoma of the prostate. A phase II trial of the Eastern Cooperative Oncology Group.

Background: Recent clinical trials have documented activity for combinations of chemotherapeutic agents that target the microtubular apparatus in patients with hormone-refractory prostate cancer. Taxol has a novel antimicrotubular mechanism, acting by stabilizing polymerized tubulin.

Methods: Twenty-three patients with hormone-refractory prostate cancer and bidimensionally measurable disease were treated with Taxol by 24-hour continuous infusion at 135-170 mg/M2 every 21 days for a maximum of 6 cycles.

Identification of an androgen-induced C3-P4 DNA binding protein in the cytosol of rat ventral prostate.

A DNA binding protein C3-P4 was detected in the rat ventral prostate cytosol by gel retardation assay using a 32P-labeled 31 base pair synthetic oligomers (sequence deduced from the rat prostatic steroid binding protein C3-1 gene promoter -149 to -119) as a probe. The DNA binding activity of C3-P4 DNA binding protein is sequence specific, with preference for single strand and coding strand exclusive. This protein can be detected in many androgen target tissues and controlled well by androgen in the rat ventral prostate, we speculate that this DNA binding protein may function as an accessory factor to androgen receptor (AR) for the regulation of the C3-1 gene expression.

Characteristics of the glutathione/glutathione-S-transferase detoxification system in melphalan resistant human prostate cancer cells.

Glutathione (GSH) and glutathione-S-transferases (GST) have been implicated in resistance of tumor cells to certain alkylating agents, including melphalan. Glutathione levels and GST activities were determined in melphalan-resistant sublines of the human prostate carcinoma cell lines DU 145, PC-3 and LNCaP produced by serial treatment with melphalan at progressively increasing concentrations. The resistant sublines M4.

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

Background: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice.

Evidence of an absorption phase after short intravenous suramin infusions.

Suramin was given as an intravenous infusion to 16 cancer patients in a phase I trial. Individual pharmacokinetic parameters were calculated from a test dose given 1 week prior to the administration of a full-dose (350-700 mg/m2) regimen of 1-h loading and maintenance infusions. A distribution phase of 3.

A comparison of knowledge and communication skill evaluations by written essay and oral examinations in preclinical medical students.

While both oral and written communication skills are important in the daily work of physicians, medical school evaluation methods focus on content of written essays or often answers to multiple choice questions. To determine the feasibility and value of oral examinations for preclinical medical students, we gave a written short essay examination and an oral examination on the same question to 106 second-year medical students in a required neoplastic diseases course. Examination performance by each method was evaluated according to the same specific content and, separately, based on four communication skills criteria.

Effects of suramin on the proliferation of primary epithelial cell cultures derived from normal, benign hyperplastic and cancerous human prostates.

Primary epithelial cultures (PECs) derived from normal, benign hyperplastic (BPH), and cancerous human prostate tissue were treated with increasing doses of suramin, and assayed for cell proliferation over a period of days. The suramin IC50 (inhibitory concentration 50%) value was 0.5 to 1.

Disruption of mitochondrial function by suramin measured by rhodamine 123 retention and oxygen consumption in intact DU145 prostate carcinoma cells.

Suramin, an antiparasitic drug, has shown antitumor activity in humans. This may occur in part through disruption of energy balance, which is believed to be part of its antiparasitic action. Suramin disrupts mitochondrial function in intact DU145 prostate carcinoma cell monolayers as seen by its causing the release of rhodamine 123 from prestained cells beginning at about 10 microM in 96-well microtiter plates measured with a fluorescent plate scanner.

Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days.

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity in in vitro and in in vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study.

Increase in gamma-glutamylcysteine synthetase activity and steady-state messenger RNA levels in melphalan-resistant DU-145 human prostate carcinoma cells expressing elevated glutathione levels.

The biochemical and molecular basis for the elevation of glutathione (GSH) levels commonly detected in many drug-resistant cells has not been elucidated. In a series of L-phenylalanine mustard-resistant human prostate carcinoma cell lines (DU-145), resistance was associated with elevated GSH levels, increased activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH biosynthesis, and a marked increase in the steady-state levels of GCS-specific transcripts (4.0 and 3.

A pilot trial of chemohormonal therapy for metastatic prostate carcinoma.

Fifteen patients with previously untreated metastatic prostate cancer were treated on a pilot trial with a combination of maximal androgen blockade plus intermittent cytotoxic therapy after androgen priming to stimulate cell division. Androgen blockage was carried out using a gonadotropin-releasing hormone analog (leuprolide) plus a nonsteroidal antiandrogen (flutamide). Carboplatin (CBDCA) (800 mg/m2) was given intravenously every 28 days, preceded for 3 days and followed for 3 days by androgen treatment with fluoxymesterone (5 mg orally twice a day), during which time flutamide was discontinued.

A phase I trial of 5-fluorouracil, leucovorin, and dipyridamole given by concurrent 120-h continuous infusions.

A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m2 daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated.

The importance of steroid hormones in prostate cancer.

Steroid hormones have an important role in prostate biology. Androgens are crucial for the normal development of the prostate gland and in maintaining its functional state in the adult. It seems that the prolonged presence of androgens might also be an important factor in the development of prostate cancer.