Concomitant botanical medicine use among patients participating in commercial prostate cancer trials.

OBJECTIVES: Patients with cancer frequently use botanical medications. The concomitant use of such medications by patients on commercial trials has not been well-described, despite the importance of these trials for evaluating the safety and efficacy of new agents. We sought to describe the use of botanical medications taken by patients with prostate cancer enrolled on global commercial trials. DESIGN: Retrospective study. SETTING: Regulatory repository of commercial clinical trial data. INTERVENTIONS: Anti-cancer therapy. MAIN OUTCOME MEASURES: Botanical and medication use data were pooled across six international commercial randomized trials for metastatic prostate cancer with detailed information on medication and indications. Botanical products were considered to have potential for drug interaction if they led to a change in drug exposure in human trials. Potential for interaction was ascertained by PubMed review. Descriptive statistics were used for analysis. RESULTS: Of 7318 enrolled patients, 700 (10 %) reported botanical use at any time and 653 (9%) reported use of botanical products while on trial. Nearly half of botanical product types were not classified by plant (43 %). The highest proportion of botanical use was among patients in Asian countries (32 %), followed by patients in North America (13 %). Eighty-six different types of botanical products were used; of these, nineteen had a patient-reported anti-cancer indication. CONCLUSIONS: Botanical medicine use among patients with prostate cancer in commercial trials is moderate, although it varies by region. Practitioners should be aware of the use of botanical interventions in a clinical trial context.

Truth-telling and patient diagnoses.

How do physicians handle informing patients of their diagnoses and how much information do patients really want? How do registered nurses view both sides of this question? Three questionnaires were constructed and administered in a mid-size hospital in New York state. Physicians and nurses underestimate the number of patients who want detailed information. Patients who earn more than average, have a college education, and who are under age 60 are more likely to want information, and state that their physician should give it to them. Only 42% of physicians state that patients want a detailed description of their diagnosis and treatment options. Physicians educated outside the USA appeared to be more likely to change their criteria for informing patients and, along with American-educated nurses, were more willing to participate in formal discussions of the issue. Physicians should comply with the wishes of patients for information and include them in the team deciding on diagnosis and treatment.

Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia.

The course of essential thrombocythemia (ET) is complicated by bleeding, major thrombosis, and microvascular complications. Because about one-half of ET patients remain asymptomatic long term, the decision to use aspirin acetylsalicylic acid, (ASA) or myelotoxic drugs has not yet been clearly established. While vasomotor symptoms are improved by small doses of ASA, higher doses (900 mg/day) induce an unacceptable rate of serious hemorrhagic complications in patients with polycythemia vera. This retrospective study evaluates the utility of therapy in preventing thrombosis in ET and the efficacy and a safety of 100 mg/day of ASA in these patients. One hundred ninety-five consecutive patients with ET diagnosed in agreement with the Polycythemia Vera Study Group (PVSG) criteria are evaluated. All vascular complication before, at, or after diagnosis were recorded and related to the treatment used: no therapy, ASA alone, myelosuppressive agents or both. All treated patients had a significant reduction of thrombotic complications without increased hemorrhagic complications, in spite of therapy adopted. In addition, a significant reduction of rethrombosis was obtained in 60 patients with a previous thrombosis. A low rate of thrombosis (5.1%) was observed during the follow-up of the 135 patients previously asymptomatic for major complications. No difference appears to exist between the use of ASA and cytotoxic drugs in preventing thrombosis and rethrombosis in ET patients. However, the possible increase of cancer and leukemia with myelosuppressive drugs is minimized in patients treated with ASA. A low dose of ASA would seem to be a safe and effective agent in ET.

Morphology, growth, and gene expression in five newly isolated murine hepatocellular tumor cell lines.

Five murine hepatocellular tumor cell lines (HepM-1-5) were isolated and grown in a synthetic medium added with hormones, growth factors and/or serum. The morphology of these lines ranged from a nearly homogeneous epithelial-like shape (HepM-2) to a stromal appearance (HepM-1). The remaining lines displayed a mixed morphology. For their proliferation all of the cell lines retained a clear dependence on the extracellular calcium level and hormonal and/or serum growth factors and, rather homogeneously, they did not express the albumin, alpha-fetoprotein (with the exception of HepM-2 cells), tyrosine aminotransferase, and ornithine transcarbamylase genes, whereas they all exhibited discrete levels of the ornithine aminotransferase mRNA. Only HepM-3 and HepM-5 lines expressed the procollagen type I gene.

A novel approach to extend the survival of skin xenografts without entailing general immunosuppression or systemic toxicity.

The feasibility of using antigenically disguised skin xenotransplants to cover extensive burns for a suitable time lag without administering immunosuppressive drugs was tested experimentally. Pieces of human skin that had been preincubated for 3 h at 37 degrees C with either mouse anti-human beta 2-microglobulin monoclonal antibody (beta 2m-McAb) or PBS (controls) were grafted onto the backs of immunologically competent Swiss mice, and the time required for their rejection or substitution by normal autogenous skin was determined. Thus, it was found that the beta 2m-McAb-pretreated xenografts had a significantly longer mean survival time than the control grafts. An even longer skin xenograft MST was obtained when beta 2m-McAb was repeatedly injected, at weekly intervals, just beneath the transplants. Parallel immunohistochemical studies showed that the beta 2m-McAb entered the grafts and was bound to its targets both in epidermis and dermis. Moreover, a small amount of beta 2m-McAb administered at the outset significantly hindered the reactive proliferation of primed mouse spleen cells cultured in the presence of human epidermal cells. Finally, neither toxic effects nor a weakening of immune competence were elicited by repeated intraperitoneal injections of beta 2m-McAb. Therefore, it seems expedient to propose the use of beta 2m-McAb to delay the rejection of skin xenografts as this antibody harmlessly prevents, wholly or in part, the activation of the recipients' lymphocytes. This would positively aid any patient urgently needing xenograft cover of extensive burns.

The in utero initiation with DMN alters the complement of cytosolic glutathione S-transferases and the phenobarbital-induced expression of c-jun and c-myc oncogenes in primary neonatal rat hepatocytes.

As revealed by a novel in utero-in vitro hepatocarcinogenesis model, a single exposure to dimethylnitrosamine (DMN) elicited in postnatal (and fetal) primary rat hepatocytes (i) immunocytochemically detectable, widespread increases in their complement of the alpha, mu and especially pi classes of cytosolic glutathione S-transferases (GSTs); and (ii) changed patterns (with respect to controls) of the phenobarbital (PB)-evoked increases in steady state levels of c-jun and c-myc mRNA's. These results indicate that DMN causes both transient cytotoxic effects and a broad, permanent initiation in fetal proliferating hepatocytes.

Thein utero initiation with DMN alters the complement of cytosolic glutathione S-transferases and the phenobarbital-induced expression ofc-jun andc-myc oncogenes in primary neonatal rat hepatocytes.

As revealed by a novelin utero-in vitro hepatocarcinogenesis model, a single exposure to dimethylnitrosamine (DMN) elicited in postnatal (and fetal) primary rat hepatocytes (i) immunocytochemically detectable, widespread increases in their complement of thealpha, mu and especiallypi classes of cytosolic glutathione S-transferases (GST's); and (ii) changed patterns (with respect to controls) of the phenobarbital (PB)-evoked increases in steady state levels ofc-jun andc-myc mRNA's. These results indicate that DMN causes both transient cytotoxic effects and a broad, permanent initiation in fetal proliferating hepatocytes.

The exposure of carcinogen-initiated primary neonatal rat hepatocytes to tumor promoters modulates both the transcripts and the enzymatic activity of nuclear poly(ADP-ribose) polymerase.

Four tumor promoters, i.e. PB, TPA, NAF, and DDT, added singly to a calcium-deprived synthetic medium, elicited early and late mitogenic effects and concurrent surges of nuclear poly(ADP-ribose) polymerase (pADPRP) activity in primary neonatal rat hepatocytes mutagenized with an intra-uterine dose of DMN. These actions were fully abated by the pADPRP inhibitor 3-MBA. Conversely, EGF only acted as a full mitogen when medium's calcium was at physiological levels, and its effects could not be blocked by 3-MBA. The same tumor promoters, but not EGF, also evoked a swift and lingering amplification of pADPRP transcripts in DMN-initiated hepatocytes kept in low-calcium medium. Hence, a coordinated modulation of both pADPRP transcripts and activity by xenobiotics is likely to be involved in the clonal expansion of early preneoplastic hepatocytes.

Inhibitors of ADP-ribosyl transferase suppress the mitogenic actions exerted by tumour promoters, but not those evoked by peptide mitogens, in primary neonatal rat hepatocytes.

A significant stimulation of the 24-h (between day 4 and 5 in vitro) new DNA synthetic activity was elicited in primary neonatal rat hepatocytes kept in low-calcium (0.01 mmol/l) HiWoBa2000 synthetic medium by the addition of a single dose (10(-10) mol/l) of each of several tumour promoters [i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital, nafenopin, saccharin, teleocidin, benzoyl peroxide butylhydroxytoluene (BHT), dichlorodiphenyltrichloroethane (DDT), lindane, clofibrate and melittin]. Even hormones [e.g. epidermal growth factor (EGF), glucagon and insulin at 10(-10) mol/l] and EGF-like acting drugs (i.e. imidazole and indomethacin, at 10(-11) mol/l) similarly enhanced with respect to untreated controls the 24-h flow into S phase of the primary hepatocytes on condition, however, that the cells were incubated in a high- (i.e. 1.8 mmol/l) and not a low-calcium HiWoBa2000 medium. Xenobiotics, peptide mitogens and EGF-like acting drugs also enhanced the in vitro hepatocellular mitotic activity. The growth-stimulatory effects of the aforementioned eleven tumour promoters were entirely suppressed by the simultaneous addition to the growth medium of a fully effective dose (10(-4) - 10(-3) mol/l) of agents, such as 3-aminobenzamide (3-ABA), 3-methoxybenzamide (3-MBA) or nicotinamide (NA), that are known to inhibit the activity of ADP-ribosyl transferase (ADPRT). However, under the same conditions these inhibitors hampered neither the basal DNA synthetic and mitotic activities of spontaneously cycling hepatocytes nor the stimulation of the hepatocellular growth processes evoked by peptide mitogens and EGF-like acting drugs. Quantitative autoradiographic investigations showed that the incorporation of the ADP-ribose precursor and ADPRT substrate [3H]NAD into nuclear macromolecules of gently digitonin-permeabilized hepatocytes was negligible in the untreated cultures, whereas it was strikingly and nearly steadily increased by a 2-, 8- and 24-h exposure to a fully mitogenic dose (10(-10) mol/l) of TPA, thereby revealing that an early, significant and roughly steady activation of the nuclear ADPRT had taken place in the phorbol ester-treated liver parenchymal cells. The simultaneous addition of 3-ABA (10(-4) mol/l) not only fully checked the mitogenic effects of TPA, but even suppressed about two-thirds of the TPA-elicited nuclear incorporation of [3H]NAD by the permeabilized hepatocytes, thus showing that a significant curtailment of the TPA-activated ADPRT did occur is association with the abatement of the mitogenic effects of TPA by this inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of corticotrophin (ACTH1-24), cyclic AMP and TPA (12-O-tetradecanoyl phorbol-13-acetate) on DNA replication and proliferation of primary rabbit adrenocortical cells in a synthetic medium.

ACTH1-24 stimulated the parenchymal cells in cultures of rat adrenal cortex in serum-free synthetic HiWoBa 2000 medium to replicate DNA, enter mitosis and divide. But ACTH's principal mediator, cyclic AMP, was not a complete mitogen: the adenylate cyclase-stimulating cholera toxin and dibutyryl cyclic AMP stimulated parenchymal cells to replicate DNA but not to enter mitosis. Thus, there must have been an additional mediator of the response to ACTH1-24 that enabled the parenchymal cells to enter mitosis. This additional mediator might have been protein kinase C because a protein kinase C activator and cyclic AMP elevator, TPA, stimulated the adrenocortical parenchymal cells to replicate DNA, enter mitosis and divide.