G. A. Nagel

Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate.

Postmenopausal patients with metastatic breast cancer were treated with medroxyprogesterone acetate (MPA) (Clinovir) in dosages between 500 and 1500 mg orally per day. The relation of MPA plasma concentrations and endocrine effects were studied in a longitudinal fashion. MPA exerted suppressive effects on the basal and gonadotropin‐releasing hormone (GnRH) stimulated gonadotropin secretion, cortisol, dehydroepiandrosterone (DHEA), and estradiol (E2) in a dose‐dependent manner leading to a complete suppression with 1500 mg orally per day. The depression of thyroid hormones (T3 and T4) coincided with a depression of the thyroxine‐binding index (TBI). MPA did not affect human growth hormone (hGH), basal and thyrotropin‐releasing hormone (TRH) stimulated thyroid‐stimulating hormone (TSH) and aldosterone. Basal and TRH‐stimulated prolactin (PRL) secretion showed a slight but distinct elevation. From these data it is concluded that in postmenopausal patients MPA exerts its antitumor activity by an interference with the hypothalamo—pituitary adrenal axis in the sense of a selective pharmacologic hypophysectomy leading to complete suppression of adrenal steroid secretion. Additionally, MPA inhibits tumor cell growth through the progesterone receptor. A dual mechanism for the antitumor activity of high dose is postulated MPA: ablative through suppression of the hypothalamo—pituitary—adrenal axis and subsequent estrogen deprivation, and additive via the progesterone receptor directly on the tumor cell. The significance of gonadotropin suppression in the postmenopause for breast cancer growth is unclear. The depression of T3 and T4 is due to a depression of thyroid hormone‐binding proteins. The elevation of PRL secretion may be explained by a slight estrogenic activity of MPA metabolities.

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.

Distribution and metabolism of hexadecylphosphocholine in mice

Distribution and metabolic fate of radiolabeled hexadecylphosphocholine (He-PC) has been studied in mice. It is demonstrated that He-PC is well-absorbed from the intestinal tract, intravenous (IV) and oral administration lead to similar distributions throughout the body, the highest accumulation of radioactivity occurs in liver, lung and kidney, and the metabolic products are radioactive choline, phosphocholine and 1,2-diacylphosphatidylcholine. The occurrence of these metabolites indicates that phospholipases C and D may be involved in He-PC breakdown.

Intralesional application of recombinant human tumor necrosis factor alpha induces local tumor regression in patients with advanced malignancies

Fourteen patients with different advanced solid tumors were treated by intratumoral application of recombinant human tumor necrosis factor alpha. In five patients, local tumor regression occurred. However, the duration of response was short, implying a rapid development of resistance to rTNF-alpha application. The main clinical side-effects, including chills, fever, anorexia and fatigue, were similar to systemic rTNF-alpha treatment. Cardiovascular, pulmonary or metabolic toxicities were not observed. This study demonstrates that a high concentration of rTNF-alpha at the tumor site has the potential to induce local tumor regressions and, therefore, seems more reasonable for further clinical investigations, especially in combination with other cytokines.

Double-blind randomised trial of the antiemetic efficacy and safety of ondansetron and metoclopramide in advanced breast cancer patients treated with epirubicin and cyclophosphamide

Ondansetron was compared with metoclopramide for antiemetic efficacy in a randomised double-blind trial in 122 patients with advanced breast cancer. All patients were treated with epirubicin (greater than 50 mg/m2) and cyclophosphamide (greater than 500 mg/m2). 50 patients receiving ondansetron and 60 with metoclopramide were considered evaluable. Ondansetron was at least as effective as metoclopramide in the control of vomiting and nausea. The percentage of patients with complete plus major control was 72% (59-85%) vs. 61% (48-74%) on day 1 (P = 0.230) and 79% (67-91%) vs. 66% (53-78%) on days 2-3 after chemotherapy (P = 0.122). Over the 3-day study period, nausea was absent or mild in 60% of the patients treated with ondansetron, compared to 45% given metoclopramide (P = 0.064). No major drug-related side-effects were reported. 1 patient receiving ondansetron experienced gastrointestinal disturbance and headache. Episodes of diarrhoea, fever, hyperkinetic syndrome, fatigue, restlessness and migraine with vomiting were reported by 5 patients treated with metoclopramide. None of the changes in the biochemical or haematological parameters was attributed to the antiemetic treatments.

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.

Blut-Hirnschranke und Penetration von Zytostatika

The penetration of 12 commonly used anticancer agents through the blood-brain barrier (BBB) was measured in a rat model using a single-injection tissue-sampling technique. Two of the tested drugs penetrated the barrier, but only to a limited extent. Entry of the drugs into the brain tissue critically depends on molecular weight and lipophilia of the respective test compound. For drugs with a molecular weight of less than 500, BBB simply behaves like an oil/water interphase, whereas drugs with a molecular weight greater than 500 are practically excluded from transport through the BBB even if they show a favourable oil/water partition coefficient. However, permeability of cytostatics was strongly increased if short chain alkylglycerols, up to final concentrations of about 0.3 mol/l were added to the injected solution. Under these conditions the Brain-Uptake-Index (BUI) reached values up to about 50% (cyclophosphamide), depending on lipid solubility and molecular dimension of the respective test compound and the alkyl chain length of the glycerol derivative.SummaryThe penetration of 12 commonly used anticancer agents through the blood-brain barrier (BBB) was measured in a rat model using a single-injection tissue-sampling technique. Two of the tested drugs penetrated the barrier, but only to a limited extent. Entry of the drugs into the brain tissue critically depends on molecular weight and lipophilia of the respective test compound. For drugs with a molecular weight of less than 500, BBB simply behaves like an oil/water interphase, whereas drugs with a molecular weight greater than 500 are practically excluded from transport through the BBB even if they show a favourable oil/water partition coefficient. However, permeability of cytostatics was strongly increased if short chain alkylglycerols, up to final concentrations of about 0.3 mol/l were added to the injected solution. Under these conditions the Brain-Uptake-Index (BUI) reached values up to about 50% (cyclophosphamide), depending on lipid solubility and molecular dimension of the respective test compound and the alkyl chain length of the glycerol derivative.

Lineage- and differentiation-dependent alterations in the expression of receptors for glycoconjugates (lectins) in different human hematopoietic cell lines and low grade lymphomas

SummaryImportant biological functions and cellular recognition phenomena are supposedly governed by specific sugar-protein interactions. Human hematopoietic cell lines offer an excellent model for the study of the expression of endogenous receptors for the carbohydrate part of glycoconjugates with respect to cell lineage and modulation by differentiation. Initially, a panel of fluorescent (neo)glycoproteins was successfully employed to demonstrate cytologically the actual presence of such receptors on different cell lines: the B lymphoblast line, Daudi; the T cell lymphoblastic leukemia line, P 12; the multipotent leukemic line, K 562 and the promyelocytic line, HL 060. Biochemical analyses were performed using affinity chromatography on supports with immobilized lactose and asialofetuin (simple or complex β-galactosides), melibiose (α-galactoside), fucose, N-acetyl-D-galactosamine, maltose (α-glucoside), the mannose-rich yeast glycoprotein, mannan, glycopeptides containing sialic acid residues and heparin. Subsequently, sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis was used to detect cell lineage-dependent changes in these parameters. Differentiation-dependent changes in the expression of receptors with specificity to galactose, N-acetylgalactosamine, maltose and heparin were similarly uncovered upon dimethyl sulfoxide-induced differentiation of HL 60 cells. Differences in this type of cellular characteristic were also apparent for lymphoma cells from patients with various histological subtypes of lowgrade lymphomas. This initial description of lineage- and differentiation-dependent differences in various human hematopoietic cell lines and in cells from patients with lowgrade lymphomas suggests that advances in the knowledge of the composition of endogenous sugar receptors (lectins) may aid in understanding aspects of the biological behavior of hematopoietic cells and their related malignancies via participation of sugar-protein (lectin) interactions.

Tumor necrosis factor (TNF) alpha: control of TNF-sensitivity and molecular mechanisms of TNF-mediated growth inhibition

Tumor necrosis factor (TNF) alpha is a macrophage derived cytokine, elicited during host responses to various microbial infections. TNF-alpha exerts direct cytotoxicity towards some tumor cells in vitro and produces in vivo hemorrhagic tumor necrosis, whereas normal tissues remain unaffected (for review see [1-5]). Although the mechanisms underlying this apparent tumor-selective action remain to be defined, the prospect of a potentially powerful and selective antitumoral agent has created much interest in the identification of this biological activity, which eventually resulted in purification of the protein [6] and subsequent molecular cloning of TNF-alpha cDNA [7]. Human TNF-alpha is a non-glycosylated protein comprised of 157 amino acids (molecular weight ~ 17 kDalton), which exhibits a high specific activity ( ~ 6× 107 U/rag) in a standard in vitro cytotoxicity assay using actinomycin D-pretreated mouse fibrosarcoma cell lines [8, 9]. Sequence analysis revealed approximately 30% homology, at the amino acid level, to another cytotoxin, the lymphocyte product TNF-beta, formerly called lymphotoxin [10]. TNF-beta is a glycosilated protein comprised of 171 amino acids with a total molecular weight of approximately 25 kDalton [10, 11]. The genes for TNF-alpha and TNF-beta are tandemly arranged within the HLA gene complex on human chromosome 6 and probably are derived by duplication of a common ancestral gene [12, 13]. TNF-alpha and TNF-beta bind to the same cell membrane receptor and possess a similar, if not identical, spectrum of biological activities [14-19]. Highly purified recombinant TNF-alpha and TNF-beta produced in bacteria are nonglycosilated molecules with a molecular weight of 17 and 18.6 kDalton, respectively, which exert the same specific biological activity as their natural counterparts [7, 10]. With the availability of large amounts of highly purified recombinant human TNF (rTNF)-alpha, both clinical trials on the role of TNF-alpha in tumor therapy and extensive laboratory investigations on mechanisms of TNF-action were begun. It soon became evident that rTNF-alpha is more than a cytotoxic or tumor necrotising effector molecule. Rather, TNF-alpha appears to be a cytokine with pleiotropic activi-

Melanoma in twins. Cutaneous malignant melanoma in identical twins from a set of triplets.

Identical twins and a fraternal triplet were studied because the identical twins developed malignant melanoma at age 53. Each had a preexisting mole, nearly identically placed on the left chest, which began to grow within 2 months of one another. The homozygosity of the twins was established with high probability by appearance, behavior, psychologic testing, deficiency of color vision, red cell typing, haptoglobin typing, dermatoglyphics, lymphocyte typing, mixed lymphocyte culture, lymphocyte transfer, and skin grafting. The concordance for cutaneous malignant melanoma as well as the congruence for the site and identity of age of onset of this tumor in these monozygotic twins clearly indicates the predominant role of genetic rather than environmental factors in the development of their cancers (congruent contemporaneous concordance). Furthermore, the observation suggests that the initial phenomenon eventually leading to malignant melanoma occurred in the conceptus prior to twinning. This finding is relevant to understanding the etiopathogenesis of malignant melanoma in man.