Comparison of the tissue distribution of hexadecylphosphocholine and erucylphosphocholine.
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Animals↗
Biomedical subjects
C Unger
Publications and source records attributed to C Unger.
Hexadecylphosphocholine in the topical treatment of skin metastases in breast cancer patients.
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Administration, Cutaneous↗
Hexadecylphosphocholine stimulates the colony-stimulating factor-dependent growth of hemopoietic progenitor cells.
The effect of the antitumorally active hexadecylphosphocholine (He-PC) on the colony-stimulating factor (CSF)-dependent growth of human hemopoietic progenitor cells was studied. At low concentrations He-PC stimulated the CSF-dependent progenitor cell colony growth of three patients suffering from chronic myeloid leukemia (CML) and of three of six patients without hematological disorders. The stimulating effect was up to eight times that of the control using granulocyte colony-stimulating factor (G-CSF) and twofold in the case of granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas only slight effects were noted when interleukin 3 (IL-3) or the combination of the CSFs was used as an additive. The stimulatory effects observed are far below the He-PC concentrations that are usually required for the in vitro growth arrest of cancer cells. At higher concentrations He-PC displayed suppressive effects, most pronounced in the case of G-CSF-dependent colony growth. At the concentrations investigated, He-PC failed to show any changes in the composition and distribution of specific colonies. He-PC by itself had no mitogenic activity. This indicates that He-PC acts as a co-stimulator. In the cases of myeloproliferative diseases and in the case of a patient without known hematological disorder, removal of accessory cells did not abrogate the He-PC-enhanced colony growth by CSFs. Thus, the stimulatory effect of low-dose He-PC seems not to be mediated by accessory cells.
Aged↗
Long-term results of varicocelectomy.
Between 1983 and 1985, 257 infertile men were examined for any present varicocele by means of the Doppler sonography, telethermography and palpation. Based on these findings, the spermiogram and the infertility history, high ligation of the spermatic vein was indicated in 89 patients with varicocele and a median duration of infertility of 36 months (6-88 months). Postoperative sperm examinations have shown a significant improvement in sperm count and morphology, but not in motility. The most significant drop was observed in germ cell concentration from 1.68 to 1.06 mio/ml (p less than 0.025 Wilcoxon signed rank sum test). The follow-up examination 6 years after the beginning of the study has shown that only 56 out of the 89 patients underwent surgery, whereas 33 patients refrained from it. Pregnancy rates were 42% (23 out of 55, 1 patient lost to follow-up) in the operated group and 45% (14 out of 31, 2 patients lost to follow-up) in the nonoperated group. The comparison of the two graphs showing pregnancy incidence clearly demonstrates that pregnancies in the nonoperated group occur earlier than in the operated group; it has to be noted, however, that several patients only refrained from being operated on because pregnancy had occurred before surgery was planned. On the one hand, our study confirms other authors' results, i.e. that pregnancy rates in the nonoperated group are relatively high despite present varicocele. On the other hand, the operated group achieved practically the same high pregnancy rate when monitored over a longer period of time.(ABSTRACT TRUNCATED AT 250 WORDS)
Female↗
Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C.
Tumor necrosis factor (TNF) is a proinflammatory polypeptide that is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. One major pathway by which TNF receptors communicate signals from the membrane to the cell nucleus involves protein kinase C (PKC). In the present study, we have addressed the molecular mechanism of TNF-induced PKC activation. To this, membrane lipids of the human histiocytic cell line U937 were labeled by incubation with various radioactive precursors, and TNF-induced changes in phospholipid, neutral lipid, and water-soluble metabolites were analyzed by thin layer chromatography. TNF treatment of U937 cells resulted in a rapid and transient increase of 1'2'diacylglycerol (DAG), a well-known activator of PKC. The increase in DAG was detectable as early as 15 s after TNF treatment and peaked at 60 s. DAG increments were most pronounced (approximately 360% of basal levels) when cells were preincubated with [14C]lysophosphatidylcholine, which was predominantly incorporated into the phosphatidylcholine (PC) pool of the plasma-membranes. Further extensive examination of changes in metabolically labeled phospholipids indicated that TNF-stimulated hydrolysis of PC is accompanied by the generation of phosphorylcholine and DAG. These results suggest the operation of a PC-specific phospholipase C. Since no changes in phosphatidic acid (PA) and choline were observed and the production of DAG by TNF could not be blocked by either propranolol or ethanol, a combined activation of phospholipase D and PA-phosphohydrolase in DAG production appears unlikely. TNF-stimulated DAG production as well as PKC activation could be blocked by the phospholipase inhibitor p-bromophenacylbromide (BPB). Since BPB did not inactivate PKC directly, these findings underscore that TNF activates PKC via formation of DAG. TNF stimulation of DAG production could be inhibited by preincubation of cells with a monoclonal anti-TNF receptor (p55-60) antibody, indicating that activation of a PC-specific phospholipase C is a TNF receptor-mediated event.
Calcium↗
Hexadecylphosphocholine-mediated enhancement of T-cell responses to interleukin 2.
The effect of low-dose hexadecylphosphocholine (He-PC) on normal peripheral mononuclear cells (PMNC) was studied. Interferon-gamma (IFN-g) production, interleukin 2 (IL-2) receptor, and HLA-DR antigen expression were investigated, representing typical T-cell activation parameters. In PMNC cultures, He-PC dose-dependently enhanced the production of IFN-g, provided IL-2 had been added exogenously. Without IL-2 He-PC was ineffective. In some cultures, at a concentration of 8 micrograms/ml He-PC stimulated the secretion of IFN-g more than 20-fold compared to untreated controls. Although He-PC by itself lacked mitogenic activity, this compound also stimulated IFN-g production in the presence of suboptimal doses of phytohemagglutinin (PHA). Immunofluorescence studies demonstrated that He-PC also increased IL-2 receptor and HLA-DR antigen expression under these experimental conditions. Taken together, these results indicate that He-PC may possess immunomodulatory activity also in vivo, acting as a costimulator for the IL-2-mediated T-cell activation process.
Drug Synergism↗
[Prognosis of local-regional recurrence in breast carcinoma].
992 primary breast cancers were treated at the Gynaecological Department of the University Hospital of Zürich between 1971 and 1988. Local recurrence (LR) has occurred in 131 patients up to now after a median follow-up of 5.1 years. 75% of the LR manifested the first three years after operation. Especially the locoregional (axillary) recurrences occurred early. The frequency of LR was independent of the menopausal status and the steroid receptors, but was dependent on the initial axillary nodal status and the tumor size. Patients with nodal involvement had recurrences significantly more often (74 of 372 = 20%) than those without (34 of 469 = 7%). LR of patients with tumors smaller than or equal to 2 cm occurred in 7%, in patients with tumors greater than 2 cm in 17%. The 5-year survival of all patients and the patients with a LR was 80% and 57% respectively. The longer the disease-free interval, the better the prognosis of survival. The findings suggest, that especially an early LR can not be looked at as merely a local problem but rather as a signal of a systemic manifestation of the disease.
Breast Neoplasms↗
[Risk factors in breast carcinoma].
A group of 992 breast cancer patients (risk group, R) was compared with a group of 482 patients hospitalized for non oncologic reasons and matched for age and year of hospitalization (comparison group, C). The findings confirm the following factors as risk factors for breast cancer: nulliparity (R 28.8%, C 17.5%, p less than 0.001), late first birth (over 34 years of age) (R 11.4%, C 5.1%, p less than 0.001), diabetes mellitus (R 7.0%, C 3.8%, p = 0.017), hypertension (R 25.7%, C 18.1%, p = 0.0016), alcohol (R 9.4%, C 5.9%, p = 0.03), positive family history (R 14.8%, V 5.3%, p less than 0.001) and breast surgery for benign disease (R 13%, C 7.5%, p = 0.002). Frequently mentioned risk factors such as early menarche and late menopause did not emerge as risk factors in our study. Cigarette smoking did not show a protective effect but even tended to be more frequent in the risk group. Multiparity (more than 2 births) was protective (R 22.1%, C 32.4%, p less than 0.001). The findings on hormonal replacement therapy (R 7.1%, V 17.0%, p less than 0.01) might have been influenced by a selection bias (hospitalization of patients in the comparison group because of complications of hormonal replacement therapy such as bleeding) and are thus not fully conclusive. It can at least be said that hormonal replacement therapy is not more frequent in the risk group.
Adult↗
Hexadecylphosphocholine: preclinical and the first clinical results of a new antitumor drug.
Dose-response studies on cytotoxic alkyl lysophospholipids with various chemical structures revealed that a long alkyl chain and a polar group are essential for antitumor activity. The combination of both the long alkyl chain and a phosphocholine group thus results in alkyl phosphocholines. Preclinical studies with hexadecylphosphocholine (He-PC) as a representative compound indicate distinct antineoplastic activity on leukemia cells of human origin. He-PC is highly effective in inhibiting the growth of chemically induced rat mammary carcinomas. Even more striking is the fact that a high percentage of the tumors regressed completely. In a clinical phase I trial on breast cancer patients with local recurrences, topically applied He-PC resulted in regression of skin metastases. A phase II trial for topical treatment and a phase I trial for orally applied He-PC have been initiated to further evaluate the antitumoral activity of this new compound.
Adult↗
Timing of breast cancer surgery within the menstrual cycle: influence on lymph-node involvement, receptor status, postoperative metastatic spread and local recurrence.
Prompted by a report of Hrushesky et al. stating that women operated upon for breast cancer during their perimenstrual period showed a higher risk for developing future metastases than women operated upon during their mid-cycle, we examined the patients with breast carcinoma who were treated at the Gynaecological University Hospital Zürich between 1971 and 1988 with respect to the influence of menstrual cycle phase on certain factors. 104 patients underwent perimenstrual surgery, i.e., between days 1 and 6 or days 21 and 36 of the cycle. 120 women had mid-cycle surgery (i.e., days 7-20 of the cycle). In contrast to the experience of Hrushesky et al., we found no significant differences in the survival curves. The same was true when the proliferative phase (days 1-14; n = 109) was compared with the secretory phase (days 15-32; n = 108). We tested the different groups for homogeneity and found that 54% of the patients with perimenstrual surgery showed axillary lymph node involvement, whereas in the midcyclic group only 38% showed positive nodes. We have no plausible explanation for this difference. These findings indicate that there might be certain cycle-related differences with respect to lymph node status but that they do not affect survival. Hence, timing surgery to the menstrual cycle is not mandatory for the time being.
Breast Neoplasms↗
The inducible blood-brain barrier endothelium-specific antigen HT7, a novel immunoglobulin-like membrane glycoprotein.
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Animals↗
Effects of antineoplastic phospholipids on parameters of cell differentiation in U937 cells.
The proliferation of the human promonocytic leukemia cell line U937 is inhibited by several ether lipids, ether lipid analogues and by phorbol esters. An early effect of this retardation of cell growth is the induction of a basic chromosomal protein, histone H1(0). Northern blot analysis of H1(0) mRNA levels reveals an increase of the mRNA concentration within a few hours after addition of hexadecylphosphocholine and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine. This early effect on the synthesis of a subtype of H1 proteins precedes the expression of several parameters of the monocytic differentiation of U937 cells.
Antigens, Surface↗
Hexadecylphosphocholine: a new and selective antitumor drug.
Interdisciplinary cooperation between basic and clinical research has resulted in the discovery and development of alkylphosphocholines, a new class of substances for the treatment of breast cancer. In contrast to most antitumor substances, the alkylphosphocholines do not attack the cell nucleus, but the cell membrane. This report presents a systematic study which, for the first time, provides a correlation between their chemical structure, antitumor efficacy and selectivity. Through an understanding of the metabolism of tumor growth inhibiting (ether)-lysolecithins, the minimal structural requirements for the antineoplastic efficacy of these substances have been obtained. This knowledge was used to identify molecular structures which are more effective and less toxic for the organism. The active principle derived from a study of (ether)-lysolecithins active as antitumor agents represents a new class of compounds: the alkylphosphocholines. As reported here, hexadecylphosphocholine is the most promising candidate of this group of compounds. It has an extremely selective action against chemically induced, autochthonous rat mammary carcinomas. No loss of activity was observed when comparing oral and intravenous administration. Particularly striking (and favorable for long-term therapy) is the fact that immunosuppression and hematotoxicity were not found at drug concentrations which lead to complete tumor remissions. Results obtained from animal experiments have been confirmed by preliminary clinical investigations.
Animals↗
Hexadecylphosphocholine in the topical treatment of skin metastases in breast cancer patients.
Widespread local recurrence of breast cancer, untreatable by surgery or radiation therapy, can present a serious therapeutic problem predominantly in patients refractory to systemic therapy. In a phase I trial hexadecylphosphocholine, a new agent with high membrane affinity and antineoplastic activity was applied topically to affected skin areas of breast cancer patients. The results provide evidence that hexadecylphosphocholine may be an active agent in the topical treatment of skin metastases.
Administration, Topical↗
Cytotoxic activity of lysophosphatidylcholine analogues on human lymphoma Raji cells.
The cytotoxic activity of 21 lysophosphocholine analogues was tested on human lymphoma Raji cells. Structure-activity investigations revealed a more than 50-fold difference in the cytotoxicity between the different compounds. Whereas acyllysophosphocholines showed only borderline effects, the most pronounced toxic activity was observed with compounds which have an etherbond in the sn-1 position and a hydrogen, a methoxy or a methoxymethylgroup in position sn-2. Elongation of the phosphorous-nitrogen distance in the choline group markedly reduced the cytotoxicity of the compounds. From the results obtained it was concluded that a long chain fatty alcohol adjacent to a phosphocholine headgroup represents the minimal requirement for antineoplastic activity. Thus, a new group of antineoplastic compounds, the alkylphosphocholines, was developed in our laboratory, with in vitro cytotoxic activities just as effective as the most toxic alkyllysophosphocholines.
Antineoplastic Agents↗
Effect of ether lipids on mouse granulocyte-macrophage progenitor cells.
In this study we determined the potential bone marrow toxicity of the ether lipid derivatives 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (OcMe-G-3-PC), 1-0-hexadecyl-propanediol-2-phosphocholine (He-Pr-2-PC), and hexadecylphosphocholine (He-PC). OcMe-G-3-PC inhibited the proliferation of mouse granulocyte-macrophage progenitor cells (GM-CFCs) at a dose of 1 micrograms/ml, whereas He-Pr-2-PC and He-PC started to inhibit the growth of hemopoietic precursors at 5 micrograms/ml. In contrast to this finding, NMRI mice given 10 mg/kg i.v. daily for 4 weeks and 20 or 30 mg/kg for 5 days showed no bone marrow toxicity. We conclude that the dose-dependent toxic effects observed in vitro are within the physiological tolerance in vivo.
Animals↗
Hexadecylphosphocholine, a new ether lipid analogue. Studies on the antineoplastic activity in vitro and in vivo.
Hexadecylphosphocholine (He-PC) is a new compound synthesized according to the minimal structural requirements deducted from studies with other ether lipids. In vitro studies on He-PC revealed remarkable antineoplastic activity on HL60, U937, Raji and K562 leukemia cell lines. In addition, He-PC, applied orally, showed a superior effect in the treatment of dimethylbenzanthracene-induced rat mammary carcinomas when compared to intravenously administered cyclophosphamide. After oral application He-PC was well absorbed from the intestine and metabolized in the liver by phospholipases C and D. During a 5-week treatment no hematotoxic effects were detected. In a clinical pilot study on breast cancer patients with widespread skin involvement, topically applied He-PC showed skin tumor regressions without local or systemic side effects.
Animals↗
Altitude, low birth weight, and infant mortality in Colorado.
A decrease in birth weight occurs at high altitude, but its relationship to infant mortality is unclear. We examined Colorado vital statistics recorded from 1979 through 1982 to determine whether high altitude increased infant mortality and whether decreased birth weight contributed to the mortality observed. Retardation of intrauterine growth reduced birth weight and doubled the frequency of low-birth-weight infants from the lowest (915 to 1523 m [3000 to 4999 ft]) to the highest (greater than or equal to 2744 m [greater than or equal to 9000 ft]) altitude in the state. Low birth weight increased mortality risk, but the mortality risk of low birth weight was decreased at high compared with low altitudes, resulting in similar infant mortality rates throughout the state. This finding differed from that of 1969 through 1973 when infant mortality doubled at high altitude. A 46% infant mortality reduction had occurred statewide over the ten years due chiefly to decreased mortality risk for preterm low-birth-weight infants. This reduction, particularly pronounced at high altitude, might have been due to better identification and transport of high-risk pregnancies to hospitals with tertiary neonatal treatment centers.
Altitude↗