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W D Figg

Publications and source records attributed to W D Figg.

At least 55 records · Page 3Linked to original sources
PubMed2000

Suramin administration is associated with a decrease in serum calcium levels.

Suramin has been shown to have an effect on bone resorption in in vitro models. It is not clear if a similar effect is seen in patients treated with suramin. The clinical effect of suramin treatment on total serum calcium was examined in two groups of patients with hormone-refractory prostate cancer. In all, 28 patients in group 1 were examined within 2 weeks before and 2 weeks after suramin treatment and 72 patients in group 2 were examined within 2 weeks before, during, and after treatment with suramin. In addition, calcium controls spiked with suramin were run in three different commercially available assays for evaluation of the effect of suramin dose on calcium determination. Group 1 patients showed a decrease in serum calcium after treatment with suramin. The mean uncorrected serum calcium level was 2.29 +/- 0.025 mmol/l before treatment and 2.09 +/- 0.025 mmol/l after treatment (P < 0.0001, paired Wilcoxon test). The mean serum calcium value corrected for albumin was 2.33 +/- 0.02 mmol/l before treatment and 2.24 +/- 0.02 mmol/l after treatment (P = 0.0022, paired Wilcoxon test). Group 2 patients also displayed a decrease in serum calcium after treatment with suramin. The mean baseline value was 2.23 mmol/l (median 2.26 mmol/l, range 1.20-2.54 mmol/l). The mean level of serum calcium corrected for albumin as determined at the end of treatment was 2.14 mmol/l (median 2.16 mmol/l, range 0.98 2.46 mmol/l). In all, 48 patients for whom pre- and post-treatment values were available for analysis displayed a median calcium decrease of 0.09 mmol/l (P = 0.0005, Wilcoxon signed-rank test for the null hypothesis of no change). For 68 patients in group 2, data on serial serum calcium measurements during treatment were available for analysis. A projected median decrease in serum calcium of 0.06 mmol/l (range 0.43 to 0.72 mmol/l) over an 8-week interval of suramin therapy was found. Overall, 47 of the 68 slopes were negative (P = 0.0022, Wilcoxon signed-rank test). Nine patients were treated with suramin for less than 6 weeks. These patients' calcium levels were significantly higher than those of 50 patients treated for longer periods (median value 2.24 versus 2.16 mmol/l, P = 0.035, Wilcoxon rank-sum test). No correlation was found between suramin dose and calcium level using the Kodak Ektachem, Hitachi 914, or Synchron Clinical System CX3 method. In conclusion, suramin treatment was consistently associated with decreases in serum calcium in two groups of patients with hormone-refractory cancer. Suramin placed in calcium controls did not affect calcium determination using three commercially available methods.

Anti-Inflammatory Agents↗
PubMed2000

High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma.

COL-3, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, is a matrix metalloproteinase inhibitor. A specific and sensitive analytical method was necessary to quantitate the analyte in human plasma. High-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry detection was utilized to quantitate COL-3 from 30 to 10,000 ng/ml in two calibration curves: 30-1,500 and 400-10,000 ng/ml. The sample preparation consisted of acetonitrile precipitation for all plasma samples. COL-3 is separated on a Waters Symmetry C-18 (2.1 x 150 mm) column with oxalic acid (0.01 M, pH 2.2)-acetonitrile mobile phase. The total run time was 23 min. Identification of COL-3 and the internal standard was through positive chemical ionization and selective ion monitoring. A quantifying and qualifying ion for COL-3 is used to verify the presence of COL-3 in patient samples. Inter- and intra-run mean percent errors for all of the quality controls were less than 18.3', and relative standard deviations were all less than 14.9'% Recovery of COL-3 and the internal standard was approximately 55 and 72', respectively. Freeze thaw stability of COL-3 was variable. This method is suitable for quantifying COL-3 in patient samples and to further characterize the clinical pharmacology of this compound.

Antibiotics, Antineoplastic↗
PubMed2000

Activity of thalidomide in AIDS-related Kaposi's sarcoma.

PURPOSE: To assess the toxicity and activity of oral thalidomide in Kaposi's sarcoma (KS) in a phase II dose-escalation study. PATIENTS AND METHODS: Human immunodeficiency virus (HIV)-seropositive patients with biopsy-confirmed KS that progressed over the 2 months before enrollment received an initial dose of 200 mg/d of oral thalidomide in a phase II study. The dose was increased to a maximum of 1,000 mg/d for up to 1 year. Anti-HIV therapy was maintained during the study period. Toxicity, tumor response, immunologic and angiogenic factors, and virologic parameters were assessed. RESULTS: Twenty patients aged 29 to 49 years with a median CD4 count of 246 cells/mm(3) (range, 14 to 646 cells/mm(3)) were enrolled. All patients were assessable for toxicity, and 17 for response. Drowsiness in nine and depression in seven patients were the most frequent toxicities observed. Eight (47%; 95% confidence interval [CI], 23% to 72%) of the 17 assessable patients achieved a partial response, and an additional two patients had stable disease. Based on all 20 patients treated, the response rate was 40% (95% CI, 19% to 64%). The median thalidomide dose at the time of response was 500 mg/d (range, 400 to 1,000 mg/d). The median duration of drug treatment was 6.3 months, and the median time to progression was 7.3 months. CONCLUSION: Oral thalidomide was tolerated in this population at doses up to 1,000 mg/d for as long as 12 months and was found to induce clinically meaningful anti-KS responses in a sizable subset of the patients. Additional studies of this agent in KS are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.

PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.

Adult↗
PubMed2000

TNP-470: an angiogenesis inhibitor in clinical development for cancer.

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.

Angiogenesis Inhibitors↗
PubMed2000

Carboxyamido-triazole inhibits angiogenesis by blocking the calcium-mediated nitric-oxide synthase-vascular endothelial growth factor pathway.

The induction of angiogenesis is known to play a critical role in the successful growth, invasion, and metastasis of a tumor. A tumor will not grow beyond a few cubic millimeters without the formation of its own capillary network. Several antiangiogenic agents are under investigation in the clinic setting for the treatment of cancer. Carboxyamido-triazole (CAI), an inhibitor of Ca(2+)-mediated signal transduction, has been previously shown to inhibit angiogenesis in vitro and in vivo and to down-regulate matrix metalloproteinase-2 in vitro. Diminished levels of intracellular Ca(2+) result in decreased nitric-oxide synthase (NOS) activity and thereby inhibit the production and release of NO. The antiangiogenic activity of CAI was investigated by assessing microvessel growth from rat aortic segments and in cell culture using human aortic endothelial cells (HAECs). With these models, vascular endothelial growth factor (VEGF) and NOS production and secretion were evaluated. CAI concentrations ranging from 0.25 to 12.0 microg/ml inhibited new microvessel formation in rat aortic cultures and HAEC proliferation in a dose-dependent manner. Additionally, HAECs treated with CAI showed a dose-dependent decrease of NOS expression and a decrease in both VEGF expression and secretion. Rat aortic segments demonstrated decreased VEGF expression in situ on immunostaining. These data suggest that modulation of the NOS-NO-VEGF pathway through Ca(2+)-mediated signaling by CAI inhibits angiogenesis in vitro.

Animals↗
PubMed2000

Efficacy of microtubule-active drugs followed by ketoconazole in human metastatic prostate cancer cell lines.

PURPOSE: Once a relapse occurs following primary endocrine treatment, metastatic prostate cancer is one of the most therapy-resistant human neoplasms. Ketoconazole is used for complete androgen deprivation, and recent data suggest it has direct activity against prostate cancer cells. MATERIALS AND METHODS: LNCaP, DU145, and PC3 cells, human prostate cancer cell lines, and HL60, a human leukemia cell line, were lysed and soluble proteins were harvested. Cells were plated in 96-well flat bottom plates and then exposed to the pharmacological agents, ketoconazole, vinblastine and paclitaxel. DNA synthesis was monitored by 3H-thymidine incorporation. RESULTS: We demonstrate that ketoconazole exerts a cytostatic effect on a panel of human prostate cancer cell lines, with IC50 of 4 to 5 microg./ml., 12 microg./ml., and 25 microg./ml. for LNCaP, PC3/PC3M, and DU145 cells, respectively. On the other hand, using microtubule-active drugs, vinblastine and paclitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a beneficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse treatment with vinblastine. CONCLUSION: Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.

Antineoplastic Agents↗
PubMed2000

Modulation of clinical drug resistance in a B cell lymphoma patient by the protein kinase inhibitor 7-hydroxystaurosporine: presentation of a novel therapeutic paradigm.

Emerging evidence suggests that apoptosis is an important mechanism of tumor cell death from antineoplastic therapy. 7-hydroxystaurosporine (UCN-01) is a novel protein kinase inhibitor that increases chemotherapy-induced apoptosis in vitro and is in early phases of clinical development. In this report, we present a 68-year-old patient with chemotherapy-resistant lymphoma treated with UCN-01 and chemotherapy. He had a stage IV plasmacytoid lymphoma that failed to enter remission with high-dose EPOCH II (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) chemotherapy. Due to disease progression and transformation to large cell lymphoma in the liver and bone marrow, he received UCN-01. Four weeks later, he received "standard-dose" EPOCH because of progression, developed severe neutropenia for 9 days, and expired from Candida sepsis on day 23. At autopsy, there was no histological evidence of residual lymphoma, although PCR for immunoglobulin gene rearrangement analysis revealed a faint clonal band in two of six nodes but none in the liver. Significantly, no B cells were detected by immunohistochemistry in lymph nodes, and a polyclonal ladder pattern associated with the presence of normal B cells was not seen in the immunoglobulin gene rearrangement PCR assay. Profound peripheral lymphopenia (50 cells/microliter) was also observed. Pharmacokinetics showed UCN-01 salivary concentrations, a surrogate for free drug concentrations, to be within an effective range in vitro (45 nmol/L) as a modulator of DNA-damaging agent cytotoxicity. In vitro, UCN-01 is synergistic with multiple cytotoxic agents and increases fludarabine-induced apoptosis in a human breast cell line. These results suggest that UCN-01 sensitized the lymphoma to the cytotoxic effects of EPOCH, possibly by modulating the "threshold" for apoptosis, and may illustrate a new paradigm for reversal of drug resistance.

Aged↗
PubMed2000

A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma.

This study used an 8-day continuous infusion regimen of a 1:1 mixture of two immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA; Combotox) in a Phase I trial involving 22 patients with refractory B cell lymphoma to determine the maximum tolerated dose, clinical pharmacology, and toxicity profile and to characterize any clinical responses. Adult patients received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No intrapatient dose escalation was permitted. Patients with > or =50 circulating tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345 ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that included two deaths probably related to the IT. Additionally, patients exhibited a significant potential for association between mortality and a history of either autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and between mortality and a history of radiation therapy (P2 = 0.036). In patients with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37-dgA. In addition, HD37-dgA thawed at the study site tended to contain significant particulates, which were not apparent in matched controls stored at the originating site. This suggests that a tendency to aggregate may have resulted from shipping, storage, and handling of the IT that occurred prior to preparation for administration. It is not clear to what extent, if any, the aggregation of HD37-dgA IT was related to the encountered clinical toxicities; however, the potential to aggregate does suggest one possible basis for problems in our clinical experience with HD37-dgA and leads us to the conclusion that non-aggregate-forming formulations for these ITs should be pursued prior to future clinical trials.

Adult↗
PubMed2000

Comparative study of the clinical efficacy of two dosing regimens of flutamide.

PURPOSE: We performed a randomized trial to compare the efficacy and toxicity of a new dose of flutamide (500 mg QD) with the currently recommended dose (250 mg q8h) in the treatment of advanced prostate cancer. The primary endpoints were percent of patients having normalization of prostate specific antigen (PSA), time to normalization, and percent change from baseline. Secondary endpoints were quality of life and toxicity. PATIENTS: Altogether, 440 men aged 46 to 94 years (mean 71 years) with confirmed stage M(1) disease, documented PSA rise >0.2 ng/mL, ECOG status 0 to 2, no second neoplasm, no liver function tests > or = 1.5-fold normal values, and no previous treatment for metastatic disease were entered in the trial. RESULTS: The PSA normalized by week 12 in 71% of the patients receiving 500-mg dose and 75% of those receiving the standard dose. The percent change in PSA was 89% and 96%, respectively. The treatment groups were not significantly different with respect to the incidence of adverse events: 71% v 68% in the 500-mg and 250-mg arms, respectively (P = 0.337). CONCLUSIONS: When combined with castration, 500 mg of flutamide appears to be equally effective in lowering serum PSA and is not significantly more toxic than conventional dosing. The use of 500 mg QD instead of the standard 250 mg q8h would result in a cost savings of 30%.

Aged↗
PubMed1999

Augmentation of melanoma-specific gene expression using a tandem melanocyte-specific enhancer results in increased cytotoxicity of the purine nucleoside phosphorylase gene in melanoma.

The lineage-specific human tyrosinase promoter has been used to successfully target gene expression at the transcriptional level to melanoma cells. The tyrosinase promoter, alone and in combination with a single, or a dual, tandem melanocyte-specific enhancer, was used to regulate expression of the firefly luciferase reporter gene. Transient transfections of these tissue-specific luciferase constructs in human and murine melanoma (Pmel, B16mel) and colon carcinoma (WiDr, MC38) cell lines resulted in melanoma-specific luciferase expression that was amplified 5- and 500-fold with the addition of a single or double enhancer, respectively, to the tyrosinase promoter. When the double enhancer-promoter construct expressed the highly toxic Escherichia coli purine nucleoside phosphorylase (PNP) gene, transfection of the same cell lines followed by administration of the prodrug 6-methyl purine deoxyriboside (6-MPDR) at a concentration of 50 microM caused melanoma-specific in vitro cell killing. Within 5 days after prodrug administration methylthiazol-tetrazolium (MTT) cytotoxicity assays showed that only 15 and 9% of Pmel and B16mel cells, respectively, remained viable compared with controls. This effect was highly specific, as 90 and 96% of WiDr and MC38 colon carcinoma cells remained viable 5 days after identical treatment. This effect was a direct result of increased tissue-specific conversion of 6-MPDR to the toxic metabolite 6-methylpurine (6-MP), as documented by HPLC analysis of culture supernatants. These results show that the dual tandem melanocyte-specific enhancer provides powerful amplification of the transcriptional targeting of gene expression afforded by use of the tyrosinase promoter. This amplification translates into increased, highly specific cytotoxicity to melanoma by the PNP/6-MPDR enzyme/prodrug system and, therefore, has potential efficacy in the use of gene therapy for the treatment of metastatic melanoma.

Animals↗
PubMed1999

The androgen receptor: genetic considerations in the development and treatment of prostate cancer.

The action of androgens in the development and growth of prostate carcinomas is well documented. The androgen receptor (AR) facilitates androgen-induced regulation of genes involved in cellular proliferation and differentiation. Since the early 1940s androgen ablation has been the cornerstone of treatment for metastatic prostate cancer. Although initially highly effective, hormonal therapy is not curative, and resistant disease will ultimately prevail. Mutations that alter AR conformation, function, and regulation may provide a selective growth advantage for subpopulations of cells within the tumor that are then able to proliferate in an androgen-deprived environment. Clinically, these mutations are important because they may lead to the growth of androgen-independent tumors and progression to a refractory state. Further characterization of AR mutations will lead to a more thorough understanding of their role in the development of prostate carcinomas. This information, in addition to discovering which genes are regulated by the AR, can aid in the future development of more effective pharmacotherapy for prostate cancer.

Androgen Antagonists↗
PubMed1999

Thalidomide up-regulates prostate-specific antigen secretion from LNCaP cells.

Thalidomide has been shown to have species- and metabolic-dependent antiangiogenic activity in vitro and in vivo, suggesting its potential in treating human angiogenesis-dependent pathologies such as solid tumors. Based on promising preclinical studies, thalidomide has entered phase II clinical trials for prostate, brain, breast cancer, and Kaposi's sarcoma. However, the antiangiogenic mechanism of action is largely unresolved, as are its effects on tumor-associated gene expression, cytokine secretion, etc. We have investigated the effects of thalidomide on: 1) the secretion of prostate-specific antigen (PSA) in a human androgen-dependent prostate cell line; 2) growth and viability of human prostate cells; and 3) differential gene expression profiles of thalidomide-treated vs untreated human prostate cells. A human androgen-dependent prostate carcinoma cell line (LNCaP) and a human androgen-independent prostate carcinoma cell line (PC-3) were incubated with thalidomide 0.6, 6, or 60 microg/mL for 5-6 days. Secreted PSA from LNCaP cells was measured using a commercial enzyme-linked immunosorbant assay. Cell viability studies were conducted in both LNCaP and PC-3 cells using the same thalidomide concentrations. Furthermore, the differential gene expression of thalidomide-treated LNCaP cells was compared to that of untreated control cells using a commercially available human cancer cDNA expression array system. Thalidomide-treated LNCaP cells demonstrated increased PSA/cell levels at all concentrations tested compared to untreated control cells. Thalidomide demonstrated a cytostatic effect in LNCaP cells but had no appreciable effect on PC-3 cell viability compared to untreated control cells. Comparison of cDNA expression arrays hybridized with thalidomide-treated LNCaP cDNA probes suggests that thalidomide may up- or downregulate expression of angiogenesis-related genes, i.e., vitronectin, but these differential effects require further verification. Thalidomide over a range of doses has demonstrated nontoxic, cytostatic activity in LNCaP cells and significant upregulation of LNCaP cell PSA secretion in vitro. Furthermore, preliminary data from cDNA nucleic acid arrays of thalidomide-treated LNCaP cells suggest that thalidomide upregulates a potential angiogenic modulatory protein, the vitronectin precursor, which may eventually link thalidomide's antiangiogenic activity with modulation of angiogenic vascular integrin pathways.

Antineoplastic Agents↗
PubMed1999

Pharmacokinetics of thalidomide in an elderly prostate cancer population.

Thalidomide, a glutamic acid derivative, has recently been shown to inhibit in vitro angiogenesis, the process of formation of new blood vessels. This Phase II study examined the pharmacokinetics of thalidomide in patients with clinically progressive hormone-refractory prostate cancer. Patients (aged 55 to 80 years) were randomized to two different arms, low dose versus high dose. Patients in the low-dose group were given 200 mg of thalidomide and patients in the high-dose group received 200 mg of thalidomide, with subsequent dose escalations to 1200 mg. Serial serum or blood samples were obtained for pharmacokinetic assessment after administration of a single oral dose or multiple daily dosing of thalidomide and were assayed by reversed-phase HPLC. Pharmacokinetic parameters for both the single and multiple dosing were calculated with ADAPT II. A one-compartment model best fit the data. After single dosing, the oral clearance and apparent volume of distribution for the low-dose regimen (n = 13) were 7.41 +/- 2.05 L/h and 66.93 +/- 34.27 L, respectively, whereas for the high-dose regimen (n = 11), these values were 7.21 +/- 2.89 L/h and 165.81 +/- 84.18 L, respectively. The elimination half-lives for the low and high dose were 6.52 +/- 3.81 and 18.25 +/- 14.08 h, respectively. After the multiple dosing of thalidomide, the oral clearance and apparent volume of distribution for the low-dose group (n = 10) were 6.35 +/- 1.64 L/h and 64.63 +/- 23.20 L, respectively, whereas for the high-dose group (n = 11), these values were 7.73 +/- 2.27 L/h and 167.85 +/- 82.08 L, respectively. The elimination half-lives for the low and high dose were 7.08 +/- 1.87 and 16.19 +/- 9.57 h, respectively. For both the single and multiple dosing of thalidomide, the apparent volume of distribution and half-life were significantly higher for the high-dose group than those for the low-dose group. The higher apparent volume of distribution may be attributable to several factors, such as change in absorption, protein binding, etc. A dose-proportional increase in thalidomide steady-state concentrations was seen after multiple daily dosing of thalidomide.

Aged↗
PubMed1999

Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor.

Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.

Acetamides↗
PubMed1999

Malignant ascites as only manifestation of metastatic prostate cancer.

Prostate cancer is the most common malignancy in men in the US. Both at diagnosis and throughout the disease progression it can metastasize to multiple organs (bone and lymph being the most common). Effusions (either pleural or abdominal) are relatively uncommon, but usually occur as a result of soft tissue lesions. Herein we report on a patient with androgen independent prostate cancer and an elevated PSA with disease confined to ascites of the abdomen.

Journal Article↗
PubMed1999

A phase II trial of gallium nitrate in patients with androgen-metastatic prostate cancer.

INTRODUCTION: Due to in vitro data suggesting antitumor activity with gallium nitrate, we sought to evaluate the safety and activity in patients with androgen-independent prostate cancer. METHOD: Patients were eligible for this study if they had an ECOG performance status of < or = 2, stage D2 metastatic prostate cancer that was progressing following combined androgen ablation (medical or surgical castration plus antiandrogen) and had failed antiandrogen withdrawal. Therapy consisted of gallium nitrate (200 mg/m(2)/day) as a continuous infusion for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h). Individuals that had previously received suramin were treated at a dose of 150 mg/m(2)/day of gallium nitrate. RESULTS: Eight patients were enrolled: 4 patients at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150 mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients had progression by PSA (>50% increase over baseline). Anemia requiring transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade 4 toxicity: 1 patient developed complete blindness with partial reversal over 12 months, and another patient had pulmonary infiltrates, hypoxemia, and fever. Serious adverse events were not correlated to prior suramin exposure, or gallium plasma concentrations (total or free), but appeared to be related to cumulative cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No patients developed renal or neurological toxicity. CONCLUSION: This trial was prematurely terminated because repeated administration of gallium nitrate was poorly tolerated in an elderly population with androgen-independent prostate cancer. Gallium had modest clinical activity in this disease.

Adenocarcinoma↗