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PubMed2005

Synthesis and evaluation of long-acting D-penicillamine derivatives.

This study extends the use of two lathyrogens, ss-aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCl or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign.

Adenocarcinoma↗
PubMed1981

Pharmacologic control of surface scarring in human beings.

A hypothetical basis for control of surface scar in human beings is: lathyrism produces poorly cross-linked collagen in healing wounds; poorly corss-linked collagen is more susceptible to digestion by tissue collagenase than is normally cross-linked collagen; and colchicine stimulates tissue collagenase activity. Therefore, treatment of patients with abnormal deposits of surface scar by excising the scar, inducing lathyrism, and administering colchicine should tend to correct abnormal balance between collagen synthesis and collagenolysis and result in a small scar with improved physical properties. Ten patients with massive keloids, resistant to conventional therapy by excision, grafting, and/or intralesional injection of steroids, have been treated by excising the keloid, grafting the defect, inducing lathyrism with Beta aminopropionitrile fumurate or penicillamine and administering colchicine. Patients were followed for 18 months to five years. No toxicity or untoward side effects from therapy were observed. No patients developed recurrent keloids while undergoing treatment. All patients showed some change in the amount of scar which persisted during the period of study. This data supports the hypothesis that lathyrism and colchicine therapy exert a measurable beneficial effect on surface scar in human beings.

Adolescent↗
PubMed2005

Inhibition of breast adenocarcinoma growth by intratumoral injection of lipophilic long-acting lathyrogens.

Prevention of the formation of crosslinks and/or disintegration of already formed collagen fibrils in the tumor by known lathyrogens, beta-aminopropionitrile or D-penicillamine, may result in the weakening of tumor support, decreasing angiogenesis and promoting tumor regression. This paper reviews our studies with a single intratumoral injection of lipophilic lathyrogens and others, using a systemic administration to investigate the effect of both lathyrogens. Details of our experimental results are also given.

Adenocarcinoma↗
PubMed2000

The effects of 17 alpha-methyltestosterone on myocardial function in vitro.

Testosterone analogs have been used as performance enhancers by athletes for more than 40 yr. We asked whether the anabolic steroid 17 alpha-methyl-4-androstene-17-ol-3-one (17 alpha-MT) would affect intrinsic contractile function of the heart. Male Sprague-Dawley rats, 125-150 g, were treated with 17 alpha-MT either parenterally or orally for up to 8 wk. Intrinsic contractile function of the hearts was assessed utilizing both the isolated working heart and isovolumic perfused heart preparations. Isolated working hearts from 17 alpha-MT-treated rats had a 45% decrease in heart work attributable largely to a similarly decreased stroke volume. Isovolumic perfused hearts from treated animals had elevated left ventricular systolic and diastolic pressures at similar interventricular volumes compared to controls. Rates of ventricular pressure development (+dP/dT) or relaxation (-dP/dT) were unchanged as a result of the treatment. However, static elastance was reduced in potassium-arrested hearts from the 17 alpha-MT treatment (63% increase in interventricular pressure), consistent with a limitation being imposed on stroke volume by a decreased myocardial compliance. Hydroxyproline content of the hearts was not altered by 17 alpha-MT treatment suggesting that increased stiffness was not a consequence of collagen proliferation. Treatment of the steroid rats with beta-aminopropionitrile, a compound that inhibits lysyl oxidase, restored the left ventricular volume-pressure relationship (elastance curve) to that of control hearts. Thus, chronic treatment with anabolic steroids appears to reduce left ventricular compliance, possibly related to an enhanced activity of lysyl oxidase, and results in increased crosslink formation between collagen strands in the extracellular matrix.

Administration, Oral↗
PubMed1990

Angiographic study of induced cerebral aneurysms in primates.

Five cynomolgus monkeys treated with unilateral carotid ligation, renal hypertension, and beta-aminopropionitrile feeding were studied repeatedly by cerebral angiography to clarify the growth process of saccular cerebral aneurysms. Repeated angiography demonstrated saccular cerebral aneurysms in three of five monkeys; two aneurysms were found 15 months and a third 12 months after the operation. At autopsy, one saccular aneurysm was found to be bilocular in shape, and the others were unilocular. Fusiform aneurysms were also observed in four monkeys. Microscopic studies revealed the walls of the saccular aneurysms were very thin and consisted of fibrous tissue. In one aneurysm, the aneurysmal sac was almost obstructed by a well-organized thrombus. No evidence of intramural hemorrhage was found in any of the saccular cerebral aneurysms. The conversion of early aneurysmal changes into saccular aneurysms was found to occur abruptly, and no consistent growth rate was noted. The multiloculation of saccular aneurysms was closely related to the size of an aneurysm. The present study indicates that a saccular cerebral aneurysm may grow abruptly from one of several different kinds of early aneurysmal changes.

Aminopropionitrile↗
PubMed1977

In vitro inhibition of collagen cross links by catechol analogs.

Catechol analogs inhibit the formation of hydroxylysine-derived intermolecular collagen cross links in tissue cultures of chick embryo calvaria. Formation of intermolecular collagen cross links was measured following incorporation of [14C]lysine, reduction with sodium borohydride, and elution from an ion exchange column with a pyridine-formate gradient. Cultures grown in the presence of 10(-3) M catechol, 10(-3) M dopamine, 10(-3) M L-dopa, or 10(-3) M D,L-serine-(2,3,4-trihydroxybenzyl)-hydrazide demonstrated between 43 and 84% inhibition of hydroxylysine formation. Collagen biosynthesis was not diminished in these cultures as compared to controls without additions or with beta-aminopropionitrile when measured by collagenase digestion. The formation of hydroxylysine-derived intermolecular cross links was inhibited 34 to 93% for 5,5'-dihydroxylysinonorleucine and 7 to 71% for 5-hydroxylysinonorleucine. The catechol analogs also inhibit the activity of lysyl hydroxylase as measured by specific tritium release as triated water from an L-[4,5-3H]lysine-labeled unhydroxylated collagen substrate prepared from chick calvaria. Since catechol analogs inhibit the formation of hydroxylysine in a cell-free assay, these compounds must pass into the cells of calvaria in this culture system to inhibit intracellular hydroxylysine formation and subsequently to diminish the reducible intermolecular cross links of the newly synthesized collagen.

Aminopropionitrile↗
PubMed1989

Effects of lathyrogens on the mechanical strength of the periodontal ligament in the rat mandibular first molar.

Effects of lathyrogens such as aminoacetonitrile (AAN), beta-aminopropionitrile (BAPN) and cysteamine--known inhibitors of cross-linking of collagen--on the mechanical strength of the periodontal ligament of the rat mandibular first molar were examined by measuring the ultimate load required to extract the tooth from its socket in the dissected jaw. Single injections of AAN (40 approximately 100 mg/100 g body weight) or of BAPN (100 mg/100 g body weight) caused significant decreases of the mechanical strength 24 h after administration of the drugs but that of cysteamine (30 mg/100 g body weight) did not. Significant correlations between the dose of AAN or of BAPN and the mechanical strength were found following daily administrations of the drugs for 5 days. The relative potency of AAN to BAPN was estimated to be 4.5 by a slope ratio assay. The rapid appearance and disappearance of the effect of lathyrogens on the mechanical strength of the periodontal ligament of the rat mandibular first molar provide further evidence that the turnover of the collagen in the tissue is fast. The half-time of collagen synthesis was estimated to be approximately 3 d.

Acetonitriles↗
PubMed1985

Vascular smooth muscle cells: a major source of the semicarbazide-sensitive amine oxidase of the rat aorta.

Several methods have been used to study the distribution of the semicarbazide-sensitive amine oxidase (SSAO) within the wall of the rat aorta. After separation of the smooth muscle-containing layers of the tunica media from the connective tissue of the tunica adventitia, much higher specific enzyme activity (measured with 1 microM benzylamine) was found in homogenates of the media than of adventitia. Similar results were obtained for MAO-A (with 1 mM 5-HT as substrate). SSAO activity was also considerably higher in homogenates of cells (predominantly smooth muscle) isolated from medial tissue by enzymatic dissociation with collagenase and elastase compared with homogenates of cells (mostly of connective tissue origin) from the adventitia. Histochemical staining resulting from SSAO activity (with benzylamine as substrate) occurred predominantly and intensely over the tunica media in rat aortic sections, although some occasional staining of adventitial sites was also observed. Staining was prevented by the SSAO inhibitors hydroxylamine (1 microM) and semicarbazide (1 mM), but not by the MAO inhibitor, clorgyline (1 mM). These results indicate that SSAO is associated predominantly, although not exclusively, with the smooth muscle cells in the rat aorta. Our findings that beta-aminopropionitrile (BAPN) is a reversible, competitive inhibitor (Ki around 2 X 10(-4)M) of SSAO, in contrast to the irreversible inhibition of the connective tissue lysyl oxidase by BAPN reported by others, provides further evidence that these enzymes are not identical.

Amine Oxidase (Copper-Containing)↗
PubMed1959

New method for the rapid determination of lathyrogenic agents.

Salamander and toad embryos will develop grossly observable tumors of the notochord if they are placed for 3 or more days in a solution of the lathyrism-producing chemicals beta-aminopropionitrile or aminoacetonitrile. A technique for using tumorigenesis in amphibian embryos as a biological indicator for other lathyrogenic agents is presented.

Aminopropionitrile↗
PubMed1968

Desmosine biosynthesis: nature of inhibition by D-penicillamine.

Administration of D-penicillamine and lathyrogens such as beta-amino-propionitrile to animals markedly alters connective tissue by preventing the normal cross-linkage of elastin and collagen. It had been shown that beta-aminopropionitrile blocks the cross-linkage of elastin and collagen by preventing the initial step in cross-linkage: the conversion of lysine in peptide linkage to alpha-amino adipic-delta-semialdehyde. We show that penicillamine acts after the initial step, causing the accumulation of an elastin rich in alpha-amino adipic-delta-semialdehyde.

Adipates↗
PubMed1988

Lathyrism in laying hens and increases in egg weight.

The cause of the increased egg weight in hens with lathyrism was investigated by feeding laying birds with diets containing beta-aminopropionitrile, the toxic principle of certain legume seeds in the genus Lathyrus. There was a significant increase (P less than 0.01) in the amount of albumen in the egg owing to an increased formation of thin white. The water permeability of the shell membranes demonstrated an increased porosity and a loss of tensile strength which contributed not only to a high water uptake but also to abnormalities of the shape of eggs during 'plumping'. It was concluded that a defect in the shell membrane protein system alters the membrane's general properties and that the increased egg weight in lathyrism is a result of the defect.

Aminopropionitrile↗
PubMed2005

Collagen and elastin cross-linking: a mechanism of constrictive remodeling after arterial injury.

Constrictive remodeling after arterial injury is related to collagen accumulation. Cross-linking has been shown to induce a scar process in cutaneous wound healing and is increased after arterial injury. We therefore evaluated the effect of cross-linking inhibition on qualitative and quantitative changes in collagen, elastin, and arterial remodeling after balloon injury in the atherosclerotic rabbit model. Atherosclerotic-like lesions were induced in femoral arteries of 28 New Zealand White rabbits by a combination of air desiccation and a high-cholesterol diet. After 1 mo, balloon angioplasty was performed in both femoral arteries. Fourteen rabbits were fed beta-aminopropionitrile (beta-APN, 100 mg/kg) and compared with 14 untreated animals. The remodeling index, i.e., the ratio of external elastic lamina at the lesion site to external elastic lamina at the reference site, was determined 4 wk after angioplasty for both groups. Pyridinoline was significantly decreased in arteries from beta-APN-treated animals compared with controls, confirming inhibition of collagen cross-linking: 0.30 (SD 0.03) and 0.52 (SD 0.02) mmol/mol hydroxyproline, respectively (P = 0.002). Scanning and transmission electron microscopy showed a profound disorganization of collagen fibers in arteries from beta-APN-treated animals. The remodeling index was significantly higher in beta-APN-treated than in control animals [1.1 (SD 0.3) vs. 0.8 (SD 0.3), P = 0.03], indicating favorable remodeling. Restenosis decreased by 33% in beta-APN-treated animals: 32% (SD 16) vs. 48% (SD 24) (P = 0.02). Neointimal collagen density was significantly lower in beta-APN-treated animals than in controls: 23.0% (SD 3.8) vs. 29.4% (SD 4.0) (P = 0.004). These findings suggest that collagen and elastin cross-linking plays a role in the healing process via constrictive remodeling and restenosis after balloon injury in the atherosclerotic rabbit model.

Aminopropionitrile↗
PubMed1995

Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function.

The fibrillar collagen network is postulated to be a primary determinant of left ventricular diastolic stiffness. This hypothesis was tested by examining the structural and physiological effects of a reduction in fibrillar collagen content and cross-linking in the intact left ventricle. Collagen cross-linking was inhibited by treating five normal adult pigs with beta-aminopropionitrile (BAPN; 10 g/day po) for 6 wk; five normal untreated pigs served as controls. Left ventricular volume, mass, and function were determined by simultaneous echocardiography and catheterization. Chamber stiffness, defined by pressure vs. volume data, and myocardial stiffness, defined by stress vs. dimension data, were determined from variably loaded beats during dextran infusion. Collagen distribution (% area) and integrity (% confluence) were determined by light microscopy. Collagen content was measured by hydroxyproline assay, and collagen cross-linking was measured by salt extraction. BAPN decreased collagen distribution (% area decreased from 12 +/- 1% in control to 7 +/- 1% in BAPN, P < 0.05), collagen integrity (% confluence decreased from 8 +/- 1% in control to 4 +/- 1% in BAPN, P < 0.05), collagen content (from 36 +/- 2 mg/g dry wt in control to 27 +/- 2 mg/g dry wt in BAPN, P < 0.05), and collagen cross-linking (extractable collagen increased from 21 +/- 2% in control to 28 +/- 2% in BAPN, P < 0.05). BAPN decreased chamber stiffness (0.13 +/- 0.02 in control to 0.06 +/- 0.01 in BAPN, P < 0.05) and myocardial stiffness (10.4 +/- 0.5 in control to 6.6 +/- 0.5 in BAPN, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopropionitrile↗
PubMed2005

Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism.

We have previously shown that lysyl oxidase (LOX) mRNA is up-regulated in invasive breast cancer cells and that catalytically active LOX facilitates in vitro cell invasion. Here we validate our in vitro studies by showing that LOX expression is up-regulated in distant metastatic breast cancer tissues compared with primary cancer tissues. To elucidate the mechanism by which LOX facilitates cell invasion, we show that catalytically active LOX regulates in vitro motility/migration and cell-matrix adhesion formation. Treatment of the invasive breast cancer cell lines, Hs578T and MDA-MB-231, with beta-aminopropionitrile (betaAPN), an irreversible inhibitor of LOX catalytic activity, leads to a significant decrease in cell motility/migration and adhesion formation. Conversely, poorly invasive MCF-7 cells expressing LOX (MCF-7/LOX32-His) showed an increase in migration and adhesion that was reversible with the addition of betaAPN. Moreover, a decrease in activated focal adhesion kinase (FAK) and Src kinase, key proteins involved in adhesion complex turnover, was observed when invasive breast cancer cells were treated with betaAPN. Additionally, FAK and Src activation was increased in MCF-7/LOX32-His cells, which was reversible on betaAPN treatment. Hydrogen peroxide was produced as a by-product of LOX activity and the removal of hydrogen peroxide by catalase treatment in invasive breast cancer cells led to a dose-dependent loss in Src activation. These results suggest that LOX facilitates migration and cell-matrix adhesion formation in invasive breast cancer cells through a hydrogen peroxide-mediated mechanism involving the FAK/Src signaling pathway. These data show the need to target LOX for treatment of aggressive breast cancer.

Aminopropionitrile↗
PubMed1982

Investigations of alkaline phosphatase Ca+2-ATPase and Na+, K+-ATPase during beta-APN-induced initial bone mineralization inhibition.

Tibias of 6-day-old white Leghorn chick embryos treated with beta-aminopropionitrile (beta-APN; 0.1 mg/egg/day) for 4 days and injected with 3H-proline or 3H-tetracycline on the 11th day were analyzed for incorporation of 3H-proline and 3H-tetracycline. The incorporation of 3H-proline was comparable in the controls and beta-APN-treated embryos. However, the incorporation of 3H-tetracycline was significantly lower in beta-APN-treated embryos. The bone ash contents were also lower in the latter group. Alkaline phosphatase and Ca+2-ATPase were found to be significantly lower in beta-APN-treated embryonic bones. There was, however, no difference in the activity of Na+, K+-ATPase. The histochemical examination showed the alkaline phosphatase to be present on osteoblasts and matrix vesicle plasma membranes at the periosteal surface. The chick embryonic liver tissue showed no significant differences in the activities of any of the above enzymes. The results suggest that beta-APN-induced inhibition of the bone mineralization may be due to the bone-specific inhibition of alkaline phosphatase and Ca+2-ATPase.

Alkaline Phosphatase↗
PubMed1982

Effects of inhibitors of collagen maturation on hypertension in rats.

The effects of beta-aminopropionitrile (BAPN), an inhibitor of collagen maturation, have been examined in three models of hypertension in rats. It is shown for the first time that BAPN has a rapidly developing antihypertensive action in rats with renal (one kidney-one clip) hypertension. The compound also lowered blood pressure in spontaneously hypertensive rats. In both these experiments although BAPN lowered blood pressure it did not affect the hypertension-induced hypertrophy of the aorta. BAPN suppressed the rise in blood pressure during the developing phase of deoxycorticosterone acetate-salt-induced hypertension and in this model the compound also prevented the accompanying aortic hypertrophy. However, another inhibitor of collagen synthesis and maturation, 3,4-dehydroproline, completely suppressed aortic hypertrophy but failed to prevent the rise in blood pressure in deoxycorticosterone acetate-salt hypertension. It is concluded that: (1) BAPN may have a direct antihypertensive action, and (2) inhibition of aortic hypertrophy alone cannot prevent the rise in blood pressure in the developing phase of deoxycorticosterone acetate-salt hypertension.

Aminopropionitrile↗
PubMed1989

Spontaneous rupture of the internal elastic lamina in the rat: the manifestation of a genetically determined factor which may be linked to vascular fragility.

The spontaneous rupture of the internal elastic lamina (IEL) in various arteries occurs to different extents in different rat strains. We have quantified this phenomenon in the caudal and renal arteries and abdominal aorta in two normotensive inbred strains: the Brown Norway (BN) and Long Evans (LE) strains. At 5 weeks of age, BN rats of both sexes exhibited small numbers of interruptions in the IEL of the caudal artery, whereas LE rats did not. Postpubertal male and female BN rats presented large numbers of IEL interruptions in the caudal artery and significant numbers in the renal artery and abdominal aorta, whereas LE rats showed few in the caudal artery and none in the other arteries. Treatment with beta-aminopropionitrile (BAPN, an inhibitor of lysyl oxidase, the enzyme involved in the formation of cross-links in elastin and collagen) increased the formation of IEL ruptures in both strains in the caudal and renal artery and in the abdominal aorta in BN rats, but not in the abdominal aorta of LE rats. Apart from IEL ruptures, which were more prevalent in BN rats, no differences were observed in the ultrastructure of the aortic elastic fibers between the two strains, either in controls or in BAPN-treated rats. When male rats of both strains were made hypertensive by unilateral nephrectomy and administration of deoxycorticosterone and salt, mortality was more precocious in the BN strain although blood pressure was significantly higher in the BN strain at only one time point. The incidence of cerebrovascular hemorrhage was 48% in BN rats and 0% in LE rats. Hypertension increased the formation of ruptures in the IEL in some arteries - to a greater extent in the BN than in the LE rats. These results raise the possibility that the propensity to spontaneous rupture of the IEL, which is in part genetically determined, may reflect a latent form of vascular fragility which becomes significant in hypertension, resulting in poor survival and susceptibility to cerebrovascular accidents.

Aminopropionitrile↗
PubMed1978

Aortic lathyrism and atheroma in the rat by prolonged hyperlipidic diet.

Constant, deep, extensive aortic atheroma can be induced in rats that are athero-resistant. Two main factors are involved in this experimentation: (1) Parietal alteration following chronic experimentation with beta-aminopropionitrile (BAPN, 8 weeks) and a metabolic factor with hyperlipid diet. Electronmicroscopic examination has shown progressive lesions in the elastic framework and modifications of cells in the media with dedifferentiation into fibromyocytes and also multiply. The changes are responsible for hyperplasia of the intima as well as its thickening and collagenization. They support observations made in man during aortic aging. (2) A metabolic factor with hyperlipidic diet. This diet given at various times during intoxication causes lip deposition in the intima and substantial penetration into the media when the lesions are developing.

Aminopropionitrile↗