Charles E. Myers

A phase II study of 5-aza-2'deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer.

Aims and Background Decitabine (5-aza-2′-deoxycytidine) is an S-phase-specific pyrimidine analog with hypomethylation properties. In laboratory models of prostate cancer (PC-3 and DU-145), decitabine induces cellular differentiation and enhanced expression of genes involved in tumor suppression, immunogenicity, and programmed cell death. Methods We conducted a phase II study of decitabine in 14 men with progressive, metastatic prostate cancer recurrent after total androgen blockade and flutamide withdrawal. Decitabine was administered at a dose of 75 mg/m2/dose IV as a 1 hour infusion every 8 hours for three doses. Cycles of therapy were repeated every 5 to 8 weeks to allow for resolution of toxicity. Results Two of 12 patients evaluable for response had stable disease with a time to progression of more than 10 weeks. This activity was seen in 2 of 3 African-American patients. Toxicity was similar to previously reported experience. No significant changes in urinary concentrations of the angiogenic factor bFGF, a potential biomarker of tumor activity, were identified over time in 7 unselected patients with progressive disease. Conclusions We conclude that decitabine is a well tolerated regimen with modest clinical activity against hormone-independent prostate cancer. Further investigations in patients of African-American origin may be warranted.

Lipoxygenase Inhibition in Prostate Cancer

Multiple population-based studies show an increased risk of prostate cancer in populations that consume large amounts of animal fat. However, the molecular mechanisms linking dietary fat to prostate cancer biology remain obscure. Animal fats are typically rich sources of arachidonic acid and this fatty acid is converted to a wide range of powerful compounds including leukotrienes, prostaglandins, etc. We have shown that PC3 and LNCaP convert arachidonic acid to the 5-lipoxygenase product, 5-HETE. When the formation of 5-HETE is blocked, human prostate cancer cells enter apoptosis in less than 1 h and are dead within 2 h. Exogenous 5-HETE can rescue these cancer cells. These findings indicate that 5-HETE is a potent survival factor for human prostate cancer cells.

Cytostatic activity of phenylacetate and derivatives against tumor cells: Correlation with lipophilicity and inhibition of protein prenylation

The aromatic fatty acid phenylacetate, a common metabolite of phenylalanine, shows promise as a relatively non-toxic drug for cancer treatment. This slowly metabolized fatty acid alters tumor cell lipid metabolism causing, among other effects, inhibition of protein prenylation critical to malignant growth. In pursuit of more potent analogues, we have examined the activity of related compounds against tumor cell lines established from patients with advanced prostatic carcinoma, glioblastomas, and malignant melanoma. Like phenylacetate, derivatives containing alpha-carbon or ring substitutions induced cytostasis and phenotypic reversion at non-toxic concentrations. Potency was correlated with the degree of calculated lipophilicity of the aromatic fatty acid, and the extent of inhibition of protein prenylation. Remarkably, a parallel cytostatic activity was reported in embryonic plant cells, which respond to phenylacetate and its analogues in the same concentration range and the same rank order of lipophilicity. These data suggest that phenylacetate and its analogues may act through common mechanisms to inhibit the growth of vastly divergent, undifferentiated cell types, and provide a basis for the development of new agents for the treatment of human malignancies.

A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer : toxicity and response

Abstract Introduction: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. Objective: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 μg/ml. Methods: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 μg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. Results: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 μg/ml for 4 or more weeks. A single patient treated at 215 μg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 μg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 μg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. Conclusions: In summary, although plasma suramin concentrations were maintained below 300 μg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 μg/ml for 4 or more weeks. Therapy at 215 and 175 μg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin’s activity in hormone-refractory prostate cancer.

Central role of arachidonate 5-lipoxygenase in the regulation of cell growth and apoptosis in human prostate cancer cells

Dietary fat and the risk of prostate cancer: Prostate cancer has emerged as the most frequently diagnosed malignancy among men in the United States, taking thousands of lives every year (1). It is a multistep disease. In the United States, while there are more than 15 million men with localized prostate cancer, only 40–50,000 men will develop malignancy and die in a given year. Thus the development of the metastatic phenotype is an important rate limiting step in the natural history of prostate cancer. Through the incidence of the latent form of the diseases the same worldwide, there is significant geographic variation in the diagnosis of clinically evidence prostate cancer and mortality (2–4) suggesting involvement of environmental factors in this process. Moreover, people who migrate from low-incidence countries to high-incidence countries show increased risk of invasive prostate cancer (5–8) indicating a positive role for lifestyle factors, such as diet and nutrition.

Proapoptotic anti-inflammatory drugs

The very fact that apoptosis and nonsteroidal anti-inflammatory drugs (NSAIDs) can be linked in the same title should tell you that something unusual is happening. The image of NSAIDs among physicians is certainly discordant with that associated with cancer treatment, which usually involves administration of drugs with serious or even life-threatening toxicity. In contrast, the drugs discussed in this review, including selective cyclooxygenase-2 inhibitors, lipoxygenase inhibitors, and novel NSAID derivatives (eg, sulindac sulfone and R-flurbiprofen), offer the promise of oral, nontoxic agents able to control the progression of established prostate cancer and possibly to prevent the development of prostate cancer de novo. NSAIDs were initially developed to suppress inflammation and pain by inhibiting the production of prostaglandin E2 and its metabolites. At first glance, the fact that NSAIDs are active against prostate cancer in laboratory and clinical studies might suggest that prostaglandins play a pivotal role in prostate cancer biology. However, the story is much more complex than that. Although cyclooxygenase-mediated production of prostaglandins appears to play an important role in the biology of prostate cancer, the NSAIDs and derivatives with promising activity against prostate cancer manifest several mechanisms of action that can include direct inhibition of eicosanoid formation, indirect inhibition of eicosanoid formation by inhibiting expression of enzymes involved in eicosanoid synthesis, or by interfering with the function of cyclic guanosine monophosphate.

5-HETE congeners as modulators of cell proliferation

The synthesis and assessment of the mitogenic properties of 5-HETE congeners are reported. These studies represent an effort to develop a structure-activity profile for ligands of the 5-HETE/5-oxoETE G-protein coupled receptor(s). Many of these agents possess mitogenic activity that equals or exceeds that of racemic 5-HETE family constituents in prostate cancer cell lines.

Molecular Mechanisms of Prostate Cancer Cell Death Triggered by Inhibition of Arachidonate 5-Lipoxygenase: Involvement of Fas Death Receptor-Mediated Signals

Cancer is the result of uncontrolled cell proliferation and has emerged as one of the most frequently diagnosed challenges to human health all over the world. While formation of new cells is an integral part of cancer biology, decreased death of tumor cells has recently emerged as a focus of attention as the leading cause of deregulated tissue homeostasis resulting in cancer-related tumor burden. The cell loss factor is the major determinant of tumor growth rate with values approaching to as high as 90% in some case (1). Chemotherapeutic drugs are designed to reverse the order of cancer cell behavior by blocking cell division and/or increasing cell death. Apoptosis, or programmed cell death, is a genetically based suicide mechanism preserved through evolutionary ages (2), by which infected and damaged cells are selectively eliminated from the body in a controlled fashion without much inflammatory or bystander effects. It is the dominant mechanism of cell death in multicellular species. Drugs currently in use for cancer chemotherapy, in most cases, work by induction of apoptosis, either through membrane-localized cell death receptor-mediated signals or by the involvement of mitochondria. Other cancer-therapeutic modalities including radiotherapy, immunotherapy and hormone ablation also induce cell death by apoptosis. Tumor cells, on the other hand, are posing a threat of drug-resistance by deregulating the cell-death program (“drug neo-resistance”) or immuno-resistance by expressing cell death signal-inducing ligands on their surface to counterattack the antitumor lymphocytes.

Meeting summary: Workshop conference on endocrine therapy of advanced prostate cancer, airlie house, November 3–4, 1996

Investigators from a range of disciplines met at the Airlie House Conference Center in Warrenton, Virginia, on November 3 and 4, 1996, to discuss the biologic principles, prior data, and potential new strategies for use of endocrine therapy in advanced prostate cancer. A general goal of this workshop was to consider whether androgen deprivation of prostate cancer cells may be associated with development of dependence on other hormonal mechanisms for cellular proliferation. The initial session reviewed recent data regarding mutations of the androgen receptor that allow it to initiate transcription in response to estrogens, progestins, and antiandrogens. Evolving concepts of receptor processing and competitive interactions among receptors were presented. The next session addressed the role of estrogens on prostate cellular function and carcinogenesis. Themes included the interaction of androgens with estrogens in mediating differentiated function as well as cell proliferation. The concept that estrogens may mediate the process of carcinogenesis was reviewed. The process of programmed cell death in regulating the rate of tumor growth and the mechanistic role of bcl-2 in androgen ablative therapy were discussed. The following session reviewed data obtained over the past two decades relating to secondary hormonal therapies in prostate cancer. Presentations focused on the use of aromatase inhibitors and antiestrogens, and on withdrawal responses to antiandrogens. The final session considered the difficulties in evaluating objective responses in patients with advanced prostate cancer. A series of endpoints for potential use were identified. A clear consensus emerged that better assessment tools for evaluating pain relief and other quality of life parameters be used for trials of endocrine therapy at this stage of the disease. Side effects and morbidity from experimental therapies should be a major concern in designing new trials. The new biologic data regarding receptor mutations and tumor cell evolution do not provide compelling evidence for initiating large multicenter trials but point to the need for small phase II studies to examine potential efficacy of additional endocrine therapies. Positive results would then lead to larger multicenter trials with incorporation of more highly developed evaluative tools of assessment.