Richard S. Bockman

Prostaglandins and cancer: A review of tumor initiation through tumor metastasis

Abstract Prostaglandin is a term applied to a series of compounds derived enzymatically and nonenzymatically from 20 carbon fatty acids such as arachidonic acid (20:4). Research over the past 20 years has identified the prostaglandins as products of almost every cell although the amount and class of prostaglandin produced varies considerably with cell type. Within the last ten years additional, related products of 20:4 metabolism (operationally termed eicosanoids) have been discovered, eg. prostacyclin, thromboxanes, malondialdehyde, leukotrienes, hydroperoxy and hydroxy fatty acids. The role of these 20:4 metabolites in physiological and pathological states is currently under intensive investigation and the biological action of these compounds have been implicated in many key regulatory processes. Therefore, it is not unreasonable to predict that these potent bioregulatory compounds may have a central role in the initiation and regulation (positive and negative) of the spectrum of diseases which we functionally term “cancer”.

Gallium increases bone calcium and crystallite perfection of hydroxyapatite

SummaryGallium, 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 galliums 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 μg/mg bone in the metaphyses versus 0.21±.03 μg/mg bone in the diaphyses,P<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.

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.

Effect of gallium on bone mineral properties

SummaryGallium nitrate is biologically active in blocking bone rsorptionin vitro as well asin vivo. Administration of gallium nitrate to growing rats results in a dose-dependent accumulation of low levels of gallium in bone that is associated with specific changes in the mineral properties of bone. To elucidate in greater detail the changes induced by gallium, the properties of whole and density-fractionated bone samples from control and galliumtreated rats were examined. These studies showed that short-term treatment with gallium nitrate caused an increase in bone calcium and phosphate content. Devitalized bone powder from the gallium-treated rats was less soluble in acetate buffer and less readily resorbed by monocytes. Density fractionation analyses demonstrated that the largest proportion (76% by weight) of powdered metaphyseal bone particles from rats had a density of <2.15 g/cc. Following short-term treatment (14 days) with gallium nitrate (45 mg/kg body weight), a significant increase in the relative proportion of more dense bone (≥2.15 g/cc) was observed (24% for the control vs. 39% for the gallium-treated rats,P<0.01). In the diaphyseal samples, the largest proportion (88% by weight) of the bone powder had a density of ≥2.15 g/cc. After short-term treatment with gallium, a slight decrease in mean diaphyseal particle density was observed. Measurement of calcium accretion with45Ca in the gallium-treated rats demonstrated increased specific activity in the metaphyseal bone samples, densities=2.0, 2.1, 2.15, and 2.25 g/cc; the difference was significant only for the 2.25 g/cc fraction. Therefore, short-term treatment with gallium nitrate leads to an increase in the calcium content of mature bone with more dense (more mineralized) bone particles accumulating in the metabolically more active metaphyseal bone. The data provide greater insight into the changes in bone properties induced afterin vivo treatment with gallium nitrate. However, the physiologic mechanisms by which these changes are effected are not known.

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 Hodgkins 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 Tμ/Tγ 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 Hodgkins disease.

Characterization of two newly established human cell lines from patients with large‐cell anaplastic lung carcinoma

Two permanent cell lines, designated LU‐65 and SK‐Luci‐6, were established from large‐cell anaplastic lung cancers of two patients. Both cell lines grew as solid tumors in nude mice. The histologic pattern of the tumors in the nude mouse resembled that of the primary lung cancers in that the xeno‐transplanted tissues showed no distinctive features indicative of cell type, a finding consistent with origin from a large‐cell anaplastic lung cancer. Cells from both lines formed clones in semisolid agar. Flow cytometric analysis of SK‐Luci‐6 showed a hypertriploid stemline with a very high RNA‐index. Line LU‐65 had a hyperdiploid stemline evolving into a hypertriploid stemline with a high RNA‐index. Chromosome analysis showed aneuploidy with abnormalities and marker chromosomes in both tumor cell lines. The isoenzyme pattern of LU‐65 and SK‐Luci‐6 indicated that they were of human origin and distinct from HeLa cells or another common contaminating line. Both cell lines released biologically active agents that could have caused the neutrophilia and hypercalcemia seen in the patients.

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 FBPs effects are PG synthesis-specific.

Distinguishing features of primary hyperparathyroidism in patients with breast cancer

Thirty‐five women with breast cancer and primary hyperparathyroidism (1°HFT) were admitted to Memorial Hospital during a 25‐year period. The incidence of primary hyperparathyroidism in the breast cancer patients was similar to the incidence in the total patient population at Memorial Sloan‐Kettering Cancer Center (0.15% and 0.14%, respectively). The patients with 1°HPT disease had clinical findings which distinguished them from those patients with cancer‐related hypercalcemia. Eighty percent of the breast cancer patients with primary hyperparathyroidism had earlier stage disease (Stage 0, Stage 1, Stage 2); whereas 97% of the patients with breast cancer and hypercalcemia (not due to 1°HPT) had advanced disease. There appeared to be a trend towards improved survival in the breast cancer patients with primary hyperparathyroidism when compared to patients of similar stage of disease who did not have parathyroid disease.

The Role of Fatty Acids in Murine and Human Mammary Carcinogenesis: An In Vitro Approach

Studies with animal models for mammary tumorigenesis have demonstrated that high levels of dietary fat influences the development of mammary tumors. In the mouse model mammary tumor development is initiated either by expression of preexisting mammary tumor virus (MTV) or by exposure to chemical carcinogens. While high levels of polyunsaturated omega-6 fatty acids are known to enhance spontaneous mammary tumor development, saturated fatty acids are inhibitory to tumor development in mice (1–3). Fatty acid-induced modulation has also been observed in transplantable mammary carcinomas in mice (4–6). Because of distinct strain-dependent differences in tumorigenesis in mice that are usually accompanied by a specific preneoplastic morphologic atypia, the effects of dietary modulators on mammary cell proliferation, differentiation and tumorigenic transformation have been extensively investigated.

MODULATION OF NATURAL CELL MEDIATED CYTOTOXICITY OF T-COLONIES AND PBL BY INTERLEUKIN-2

Publisher Summary Exponential proliferation of T-cell lines developed from mitogen-stimulated T-lymphocyte clonal expansion has been found to be highly dependent upon the presence of T-cell growth factor, designated as Interleukin-2 (IL-2). Initiation of clonal expansion has been shown to be positively regulated by Interleukin-1 (IL-1) and negatively regulated by prostaglandin E2 (PGE2), which are both produced by monocyte/macrophages. The T-cell colonies used in these experiments described in this chapter were obtained from peripheral blood mononuclear cells from healthy donors. Individual T-lymphocyte colonies were removed from soft agar culture and then placed into liquid medium containing 1.0 unit per ml IL-2 until a density of 7.0 × 105 lymphocytes per ml or greater was obtained. The presence of IL-2 during clonal proliferation may have a critical impact on functional expression and T-cell colony selection. The results indicate that IL-2 causes significant augmentation of NK activity in 18 h incubation. The effect of IL-2 in the system indicates that under standard conditions of T-cell colony establishment, expression of natural cytotoxicity would be strongly promoted.