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Biomedical subjects

R S Bockman

Publications and source records attributed to R S Bockman.

At least 55 records · Page 3Linked to original sources
PubMed1987

Gallium nitrate inhibits accelerated bone turnover in patients with bone metastases.

Bone metastases are a major source of morbidity in patients with cancer. Previously, we found that gallium nitrate was a highly effective treatment for cancer-related hypercalcemia. Laboratory studies have shown that this drug inhibits bone resorption in vitro and that short-term treatment in vivo increases the calcium content of bone. We evaluated the clinical effects of gallium nitrate on biochemical parameters of increased bone turnover in 22 patients with bone metastases. Treatment with gallium nitrate for five to seven days caused a median reduction in 24-hour urinary calcium excretion of 66% relative to baseline measurements (P less than .01). Hydroxyproline (OHP) excretion was also significantly reduced (P less than .01). The greatest reduction in hydroxyprolinuria occurred in patients with high baseline excretion. Ionized serum calcium and serum phosphorous declined significantly after treatment (P less than .01 for each). Serum immunoreactive parathyroid hormone (PTH) increased significantly (P less than .01), as did serum levels of 1,25 (OH)2-vitamin D3 (P less than .05). Urinary phosphorous excretion and serum levels of 25-OH-vitamin D3 were not significantly changed. No major toxic reactions occurred as a result of this treatment. These results indicate that gallium nitrate significantly reduces biochemical parameters associated with accelerated bone turnover and that this agent may be useful for preventing pathologic conditions associated with bone metastases.

Adult↗
PubMed1987

Gallium nitrate for treatment of refractory hypercalcemia from parathyroid carcinoma.

Intractable hypercalcemia is the major cause of morbidity and mortality in patients with parathyroid carcinoma. Because gallium nitrate previously was shown to inhibit the bone resorptive activity of parathyroid hormone (PTH) in vitro, we used it to treat two patients with parathyroid carcinoma and resistant hypercalcemia. In both patients, total serum calcium levels were reduced from initial values of 3.62 and 3.77 mmol/L to posttreatment values of 2.32 and 1.45 mmol/L, respectively. Urinary excretion of calcium and hydroxyproline also declined significantly. Serum PTH levels were lower in both patients after therapy, although all levels remained markedly elevated. Nephrogenous cyclic adenosine monophosphate and tubular reabsorption of phosphate remained unchanged. These data indicate that treatment with gallium nitrate can control hypercalcemia in patients with high circulating levels of PTH. Gallium nitrate antagonizes the bone resorptive activity of PTH without altering renal effects of the hormone.

Adult↗
PubMed1987

Maintenance etidronate in the prevention of malignancy-associated hypercalcemia.

Normocalcemic patients with cancer who had been successfully treated for an episode of hypercalcemia were enrolled in a randomized, multisite, double-blind, placebo-controlled trial designed to determine the efficacy of maintenance oral etidronate in preventing the recurrence of moderate to severe hypercalcemia (serum calcium level, greater than 11.5 mg/dL [greater than 2.87 mmol/L]). Ten (40%) of 25 etidronate-treated patients and 17 (46%) of 37 placebo-treated patients had recurrence of hypercalcemia within 150 days. Although patients taking etidronate had a longer time to the development of hypercalcemia (median, 55 days vs 28 days), this was not significantly different from the control group. The high attrition rate in this trial from hypercalcemia and other malignancy-related causes represents a major difficulty in conducting studies with agents that may require prolonged administration before producing a therapeutic effect.

Administration, Oral↗
PubMed1986

Characterization of prostaglandin endoperoxide synthase from a human cell line.

Prostaglandin endoperoxide synthase has been purified from the recently established human lung tumor cell line, Lu-65. By gel filtration, the purified enzyme migrated with a relative molecular weight of 115,000, unlike the ovine enzyme, which migrated at 155,000. Two protein bands of 45,000 and 68,000 were seen when the purified Lu-65 enzyme was fractionated under reducing conditions by SDS-polyacrylamide gel electrophoresis; in contrast, purified ovine prostaglandin endoperoxide synthase showed the Mr 68,000 band under the same conditions. The purified Lu-65 enzyme showed both cyclooxygenase and hydroperoxidase activities, and metabolized [3H]arachidonic acid to 3H-labeled products that, when separated by reverse-phase HPLC, co-eluted with authentic prostaglandin D2 and prostaglandin E2. An apparent Km for arachidonic acid of 3 mM was measured for the purified enzyme, and the crude membrane-bound enzyme showed an apparent Km of 1.6 mM. Under the same conditions, an apparent Km of 17 microM was measured for the purified ovine enzyme.

Animals↗
PubMed1986

Clinical study of a new antimetastatic compound, Nafazatrom (Bay g 6575). Effects on platelet consumption and monocyte prostaglandin production in patients with advanced cancer.

Nafazatrom (Miles Laboratories, West Haven, CT) is a potent inhibitor of metastasis in several animal model systems. The compound is active whether cancer cells are injected intravenously or are allowed to spontaneously metastasize from established tumors. Before studying the antimetastatic effects of Nafazatrom in a long-term randomized clinical trial, the authors conducted a preliminary study to evaluate its toxicity as well as its effects on certain parameters hat have been associated with the biology of metastasis. Since the interaction of platelets, monocytes, and tumor cells may be important for metastasis formation, the authors serially evaluated plasma levels of factors secreted from activated platelets (beta-thrombo-globulin and platelet factor 4) that are inversely correlated with platelet survival. Products of arachidonate metabolism from monocytes were also measured since Nafazatrom is known to modulate prostaglandin production. Thirty-one patients received doses of Nafazatrom ranging from 75 to 1500 mg/m2 orally three times a day. The dose was escalated every 2 weeks. There was no toxicity at any dose level. No major antitumor responses were observed. There was no consistent change in levels of platelet factors either within individual patients or for the population as a whole. Although Nafazatrom (20 microM) decreased tritiated arachidonate incorporation into peripheral blood monocytes from normal subjects in vitro, this effect was not seen in patients treated with the drug. Release of 3PGE2 and 3HETE from cultured monocytes was also not altered by treatment with Nafazatrom. It was concluded that Nafazatrom is safe and well-tolerated up to total doses of 4500 mg/day. The data suggest that the antimetastatic activity of Nafazatrom in vivo is mediated by mechanisms other than by a decrease in platelet consumption or by modulation of arachidonate metabolism by monocytes.

Adult↗
PubMed1986

Gallium increases bone calcium and crystallite perfection of hydroxyapatite.

Gallium, a group IIIa metal, is known to interact with hydroxyapatite as well as the cellular components of bone. In recent studies we have found gallium to be a potent inhibitor of bone resorption that is clinically effective in controlling cancer-related hypercalcemia as well as the accelerated bone resorption associated with bone metastases. To begin to elucidate gallium's mechanism of action we have examined its effects on bone mineral properties. After short-term (14 days) administration to rats, gallium nitrate produced measurable changes in bone mineral properties. Using atomic absorption spectroscopy, low levels of gallium were noted to preferentially accumulate in regions of active bone formation, 0.54 +/- .07 microgram/mg bone in the metaphyses versus 0.21 +/- .03 microgram/mg bone in the diaphyses, P less than 0.001. The bones of treated animals had increased calcium content measured spectrophotometrically. Rats injected with radiolabeled calcium during gallium treatment had greater 45-calcium content compared to control animals. By wide-angle X-ray analyses, larger and/or more perfect hydroxyapatite was observed. The combined effects of gallium on bone cell function and bone mineral may explain its clinical efficacy in blocking accelerated bone resorption.

Animals↗
PubMed1986

Gallium nitrate for acute treatment of cancer-related hypercalcemia: clinicopharmacological and dose response analysis.

Current treatment of cancer-related hypercalcemia is limited by agents of limited effectiveness or excessive toxicity. Gallium nitrate is a new drug which both inhibits bone resorption and increases calcium content of bone. We have now treated 39 episodes of hypercalcemia with gallium nitrate administered as a continuous i.v. infusion for 5-7 days at 3 daily dose levels (100 and 200 mg/m2, and 50 mg/m2 by brief infusion followed by 150 mg/m2). Nadir calcium values were significantly lower (9.2 +/- 1.5 mg/dl) for patients who received the highest dose relative to patients who received the lowest dose (10.5 +/- 1.6 mg/dl, P less than 0.001). While the actual percentage of patients who achieved normocalcemia was higher at the highest dose relative to the lowest dose (86 versus 60%), this difference was not statistically significant. Mean serum concentration of inorganic phosphorous declined significantly for all patients from 2.9 +/- 0.86 mg/dl at base line to 1.8 +/- 0.66 mg/dl (P less than 0.001). Pharmacokinetic studies suggested that a threshold plasma gallium concentration of approximately 1 microgram/ml must be attained to achieve acute normalization of elevated serum calcium levels. Steady-state plasma gallium levels were attained after 48 h; there was no evidence of drug accumulation in plasma after 2 days. Effects on serum creatinine concentration were negligible, and there were no other toxic reactions. These data confirm preclinical experiments which suggested that inhibition of bone resorption by gallium nitrate is dependent upon the dose and duration of drug exposure. We conclude that gallium nitrate is effective treatment for cancer-related hypercalcemia. The drug is now being evaluated against standard treatment in a randomized, double-blind trial.

Adult↗
PubMed1985

Prostaglandin E2 induces receptive behaviors in female Xenopus laevis.

The object of this study was to examine the effects of exogenous and endogenous prostaglandin E2 (PGE2) on the sexual behavior of female South African clawed frogs, Xenopus laevis. Ticking and leg extension, which communicate sexual unreceptivity to males, were studied in intact, ovariectomized, and ovariectomized-oviductectomized females. The onset of the PGE2 behavioral effect occurs within 30 sec to 3 min of injection for intact and ovariectomized females; for ovariectomized-oviductectomized females, the latency period for the effect ranges from 10-20 min. PGE2 induced receptivity in doses as low as 0.03 microgram/frog. Injection of the prostaglandin synthesis inhibitors, indomethacin and flurbiprofen (FBP), blocked chorionic gonadotropin- (HCG-) induced behavioral receptivity, suggesting that endogenous prostaglandin synthesis may have a role in regulating female sexual behavior. Flurbiprofen blockade of HCG-induced receptivity was reversed by PGE2 administration, suggesting that FBP's effects are PG synthesis-specific.

Animals↗
PubMed1985

Metabolic effects of gallium nitrate administered by prolonged infusion.

Gallium nitrate was recently found to be effective treatment for resistant cancer-related hypercalcemia. In vitro and in vivo experiments have suggested that the drug directly inhibits calcium resorption from bone; however, the overall effects of gallium nitrate on calcium balance were unknown. We have completed metabolic balance studies in four patients who received this drug by prolonged infusion. All patients were in positive calcium balance while receiving the drug. Each patient also showed a substantial decrease in urinary calcium excretion. Serum phosphorus decreased in all four patients. There was no change in phosphorus, sodium, chloride, or magnesium balance or in creatinine clearance. We conclude that prolonged infusions of gallium nitrate reduce urinary calcium excretion and that the hypocalcemic effect of this drug is primarily due to inhibition of calcium resorption from bone. Thus, the drug may prove useful in reducing accelerated bone resorption in patients with bone metastases or chronic cancer-related hypercalcemia.

Antineoplastic Agents↗
PubMed1984

Fatty acid-induced modifications of mouse mammary alveolar lesions in organ culture.

A newly developed adult RIII mouse mammary gland organ culture system was used to examine the effects of fatty acids and a prostaglandin synthase inhibitor on the survival and/or growth of lactogenic hormone-independent mammary alveolar lesions (MAL). The number of MAL per gland that persisted in the absence of lactogenic hormones was increased in cultures treated with arachidonic acid (24.0 +/- 3.4), and was decreased after treatment with stearic acid (4.0 +/- 3.4) or indomethacin (5.0 +/- 0.6). Arachidonic acid also induced higher incorporation of [3H]thymidine into the cellular DNA of MAL containing glands. A comparison of [3H]arachidonic acid uptake into intact (MAL containing) glands and parenchyma-free fat pads revealed a selectively higher incorporation of the labeled fatty acid in the intact glands. Arachidonic acid exposure produced higher cumulative amounts (4.02 ng) of prostaglandin E2 (PGE2) which was significantly inhibited (1.66 ng) by indomethacin (p less than 0.001). In contrast, exposure to stearic acid did not lower PGE2 levels below that of controls. A concomitant increase in MAL number and PGE2 production by arachidonic acid and a decrease in both caused by indomethacin suggest that arachidonic acid conversion to PGE2 may have a facilitative role in the survival of MAL.

Animals↗
PubMed1984

Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia.

Approximately two-thirds of patients who receive the anticancer drug gallium nitrate develop mild hypocalcemia. To evaluate the mechanism of drug-induced hypocalcemia, we tested the effects of gallium nitrate upon in vitro release of 45Ca++ from explanted fetal rat bones. The drug significantly inhibited 45Ca++ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time- and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancer-related hypercalcemia with gallium nitrate administered by continuous infusion. All patients responded by a reduction of total serum calcium to normal or subnormal concentrations (13.8 +/- 1.05 mg/dl, mean +/- SD pretreatment, to 8.03 +/- 1.03 mg/dl, mean posttreatment nadir). Our results indicate that gallium nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone.

Animals↗
PubMed1983

In vivo and in vitro biological activities of two human cell lines derived from anaplastic lung cancers.

Cell lines Lu-65 and SK-Luci-6 were established from two patients with anaplastic (non-oat cell) lung cancers. These cell lines showed in vivo and in vitro functional activities that could explain the paraneoplastic syndromes which were clinically manifested. In both patients, elevated white blood cell counts occurred in the absence of any evidence of sepsis. Tumor fragments taken directly from one patient and transplanted to nude mice produced a progressive leukocytosis in the mice. Tissue culture-derived cells from both cell lines enhanced white blood cell numbers following heterotransplantation to nude mice. Cell-free extracts from both cell lines were found to enhance granulocyte-macrophage colony formation in soft agar. Greater colony formation was consistently found with the cell line (SK-Luci-6) that was derived from the patient manifesting the more marked leukocytosis. These data suggest that the tumor cells release colony-stimulating activities. Coincidently, one cell line (Lu-65) synthesized and released large amounts of prostaglandin E2 with little or no other prostaglandin product; the other cell line produced no prostaglandins. When the tumor cell lines were cocultured with explanted fetal rat bones, enhanced bone resorption with excessive calcium release occurred. Bone-resorbing activity correlated with tumor prostaglandin synthesis for the cell line releasing prostaglandin E2. An osteolytic factor that was neither prostaglandin nor parathyroid hormone was released by the SK-Luci-6 cell line. Hypercalcemia was a persistent feature only in the patient from whom the latter tumor line was derived.

Adult↗
PubMed1981

Multivariate analysis of T-cell functional defects and circulating serum factors in Hodgkin's disease.

A comprehensive immunologic and serologic analysis was performed on 31 untreated patients with Hodgkin's disease. Immune evaluations stressed T-cell functional activity and included traditional parameters (PHA responsiveness and delayed hypersensitivity skin reactivity), as well as newer functional assays (T-cell colony formation, chemotaxis, spontaneous and antibody-dependent cytotoxicity, and concanavalin A-induced suppressor cell activity (CISA). Serum factors included ferritin, prostaglandins, zinc, copper, immune complexes, and thymic hormone activity. Every patient exhibited at least one T-cell or serum abnormality. The greatest percentage of patients exhibited T-cell defects in chemotaxis (85%), colony formation (81%). and PHA reactivity (64%). Immune defects were more common with advanced disease but were not related to absolute T-cell or monocyte count, skin test anergy, or abnormalities of T mu/T gamma cell proportions. Linear relationships were identified among abnormalities in the three assays employing mononuclear cells (PHA, colony formation, CISA) which may have reflected the inhibitory influence of monocytes present in the mononuclear cell preparations. Low serum zinc correlated with marked impairment of T-cell chemotaxis. Elevated prostaglandins were associated with high PHA reactivity and with depressed colony formation. Our results indicate that many complex factors, including intrinsic T-cell defects, contribute to the impaired immunity associated with Hodgkin's disease.

Adolescent↗
PubMed1981

Lymphokine-mediated bone resorption requires endogenous prostaglandin synthesis.

Enhanced synthesis of prostaglandin (PG) E by explanted fetal rat bones was initiated by lymphocyte-conditioned media but not by physiological levels of parathyroid hormone. Rapid release of PGE from bone occurred only when the lymphokine was present. Synthesis of PGE preceded and was necessary for the bone resorption caused by the lymphokine preparation. Local production of prostaglandins in response to inflammatory cell or tumor-derived factors may in part be responsible for the localized bone loss that occurs in certain pathological states.

Animals↗
PubMed1981

Prostaglandin production by human blood monocytes and mouse peritoneal macrophages: synthesis dependent on in vitro culture conditions.

The pattern of prostaglandin synthetase products from human peripheral blood monocytes was examined. Thromboxane and prostaglandin E were found to be the major products released by monocytes/macrophages on day one of culture following cell adherence. If these cells were studied 24h after cell adherence had occurred, then thromboxane synthesis was noted to be markedly reduced and PGE was the major secretory product. A day one type pattern, i.e. high thromboxane, high PGE could be elicited from day two cultured cells if cell adherence was delayed until day two of culture. Inflammatory stimuli caused a consistent rise in PGE release from day one and day two cultures, no consistent change in thromboxane was observed. It is suggested that activation of the thromboxane synthetase pathway in monocytes and macrophages is primarily a consequence of cell adherence. Prostaglandin E and prostacyclin (PGI) appear to be the major products released in response to inflammatory stimuli. These data demonstrate that the pattern and sequence of prostaglandins synthesized are in part a function of the in vitro culture conditions, time in culture and the species studied. Further, these findings offer a possible explanation to the discrepant reports in the literature.

Animals↗