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Suspensions, emulsions, solutions, and liposomes were used as carriers to deliver drugs endolymphatically in animals. The purpose was to find which preparation was best tolerated by lymph tissue while slowly releasing the highly concentrated drugs out of nodal depots. Large unilamellar liposomes manufactured by detergent dialysis yielded the best results.
BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts. METHODS: The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided. RESULTS: AG14361 at 0.4 micro M did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours. CONCLUSION: AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
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Poly(ADP-ribose) polymerase (PARP) inhibitors enhance DNA topoisomerase I (topo I) poison-induced cytotoxicity and antitumor activity in vitro and in vivo, but the mechanism has not been defined. We investigated the role of PARP-1 in the response to topo I poisons using PARP-1-/- and PARP-1+/+ mouse embryonic fibroblasts and the potent PARP-1 inhibitor, AG14361 (Ki < 5 nmol/L). PARP-1-/- mouse embryonic fibroblasts were 3-fold more sensitive to topotecan than PARP-1+/+ mouse embryonic fibroblasts (GI50, 21 and 65 nmol/L, respectively). AG14361 caused a >3-fold sensitization of PARP-1+/+ cells to topotecan compared with a <1.4-fold sensitization in PARP-1-/- cells. In human leukemia K562 cells, AG14361 caused a 2-fold sensitization to camptothecin-induced cytotoxicity. AG14361 did not affect the cellular activity of topo I as determined by measurement of cleavable complexes and topo I relaxation activity, showing that sensitization was not due to topo I activation. In contrast, repair of DNA following camptothecin removal, normally very rapid, was significantly retarded by AG14361, resulting in a 62% inhibition of repair 10 minutes after camptothecin removal. This led to a 20% increase in the net accumulation of camptothecin-induced DNA strand break levels in cells coexposed to AG14361 for 16 hours. We investigated the DNA repair mechanism involved using a panel of DNA repair-deficient Chinese hamster ovary cells. AG14361 significantly potentiated camptothecin-mediated cytotoxicity in all cells, except the base excision repair-deficient EM9 cells. Therefore, the most likely mechanism for the potentiation of topo I poison-mediated cytotoxicity by AG14361 is via PARP-1-dependent base excision repair.
PURPOSE: Mismatch repair (MMR) deficiency confers resistance to temozolomide, a clinically active DNA-methylating agent. The purpose of the current study was to investigate the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells. EXPERIMENTAL DESIGN: The effects of AG14361, in comparison with the methylguanine DNA methyltransferase inhibitor, benzylguanine, on temozolomide-induced growth inhibition were investigated in matched pairs of MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and -deficient (HCT116, CP70, and CP70-ch2) cells. RESULTS: AG14361 enhanced temozolomide activity in all MMR-proficient cells (1.5-3.3-fold) but was more effective in MMR-deficient cells (3.7-5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increased the efficacy of temozolomide in MMR-proficient cells but was ineffective in MMR-deficient cells. The differential effect of AG14361 in MMR-deficient cells was not attributable to differences in PARP-1 activity or differences in its inhibition by AG14361, nor was it attributable to differences in DNA strand breaks induced by temozolomide plus AG14361. MMR-deficient cells are resistant to cisplatin, but AG14361 did not sensitize any cells to cisplatin. PARP-1 inhibitors potentiate topotecan-induced growth inhibition, but AG14361 did not potentiate topotecan in MMR-deficient cells more than in MMR-proficient cells. CONCLUSIONS: MMR defects are relatively common in sporadic tumors and cancer syndromes. PARP-1 inhibition represents a novel way of selectively targeting such tumors. The underlying mechanism is probably a shift of the cytotoxic locus of temozolomide to N(7)-methylguanine and N(3)-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.
From the view points of safety and efficacy of sodium guaiazulene-3-sulfonate (GAS) after oral cavity administration, the absorption behavior of GAS was investigated in rats and rabbits and following results were obtained. 1) GAS was absorbed not from oral cavity but from nasal cavity in rats and rabbits. 2) The in situ perfusion experiments revealed the existence of dose-dependent specific absorption mechanism in the rat small intestine. 3) GAS was absorbed from neither the rat stomach nor the rectum. These facts reveal that GAS transfers into the systemic circulation only through the small intestine after the clinical application to the oral cavity. And these absorption characteristics of GAS are suited for its direct action on the inflamed oral mucosa. When GAS is administered into the oral cavity, the safety is at least the same as that obtained after oral administration.
To examine the absorption mechanism of sodium guaiazulene-3-sulfonate (GAS) through the nasal and the intestinal membrane, the apparent absorption rate under the various experimental conditions was measured with the in situ perfusion method in rats, and the apparent partition coefficient of GAS was also determined. The absorption rate of GAS changed biphasically depending on the initial GAS concentration in the perfusate. At the lower concentration range (less than 1 mg/ml), the absorption rate of GAS decreased with the increased in the concentration, and the absorption was inhibited by HgCl2 and ouabain. However, at the higher concentration range (greater than 1 mg/ml), the absorption rate from the nasal mucosa increased markedly with the increase in the concentration, and ouabain had no effect. The apparent partition coefficient of GAS increased with the increase in the concentration of GAS, and GAS was found to be readily transferred to the organic phase by forming ion-pair complexes with the cation such as NH4+ ion. These results suggested that GAS is absorbed through the nasal membrane by at least two kinds of mechanisms: one is a carrier mediated system and the other is a hydrophobic interaction with the nasal mucosa which is increased by forming an ion-pair complex of GAS with cation.
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The metabolites of sodium 3-ethyl-7-isopropyl-1-azulenesulfonate (KT1-32, 1), a candidate as an anti-ulcer drug, and related compounds were synthesized. The effects of the compounds on anti-peptic activity were determined as compared to that of 1.
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We studied the effects of KT1-32 (sodium guaiazulene 3-sulfonate) on development of various acute gastric lesions and duodenal ulcers induced in rats. Male Donryu or Sprague-Dawley rats (220-270 g), fasted (but allowed free access to water) for 24 or 48 hr before the experiments, were used. KT1-32 (dissolved in distilled water, 10-100 mg/kg), given p.o. or intraduodenally (i.d.), dose-dependently inhibited the development of gastric lesions induced by HCl X ethanol (60% ethanol in 150 mM HCl), HCl X aspirin (aspirin 100 mg/kg in 150 mM HCl) or aspirin (150 mg/kg in pylorus-ligated preparation) and Shay ulcers (14 hr pylorus ligation). KT1-32 (30 and 100 mg/kg), given p.o. twice (9.5 hr apart), significantly inhibited the development of duodenal ulcers induced by mepirizole (200 mg/kg, s.c.), but did not inhibit gastric lesions developed simultaneously. KT1-32 (30 and 100 mg/kg), given p.o. or i.d., significantly reduced gastric acid secretion when examined using pylorus ligation preparations. KT1-32 (100 mg/kg, i.d.) had no effect on basal and suppressed duodenal HCO3- secretion by mepirizole. These results suggest that KT1-32 is a promising drug for the treatment of gastritis and peptic ulcers.
Azuletil sodium (AZE, 100 mg/kg, p.o.) did not affect the general behaviors, spontaneous motor activity, pentobarbital-induced hypnosis and body temperature. Furthermore, it did not elicit anticonvulsant and muscle relaxant actions. However, AZE (300 mg/kg, p.o.) elicited a stiff gate and slightly inhibited the spontaneous motor activity and electroshock-induced convulsions. It had no influence on spontaneous EEG activities, even at 30 mg/kg, i.v. AZE inhibited acetic acid-induced writhing moderately at doses above 100 mg/kg. AZE at concentrations up to 10(-5) g/ml did not affect agonist-induced contractions of the isolated ileum, trachea, vas deference and uterus, but inhibited serotonin and oxytocin-induced contraction at concentrations above 3 x 10(-4) and 10(-5) g/ml, respectively; and it also depressed spontaneous movements of the ileum and uterus at concentrations above 3 x 10(-4) g/ml. AZE caused no changes in blood pressure (BP), heart rate (HR), left ventricular pressure, ECG, tracheal pressure (TP), femoral blood flow (FBF) and coronary blood flow (CBF) at doses up to 10 mg/kg, i.v. in anesthetized dogs, but it caused an increase or a decrease in BP, an increase in TP and an increase in CBF at 30 mg/kg, i.v. However, even at 300 mg/kg, p.o., it caused no changes in BP and HR in conscious rats. AZE moderately promoted the charcoal transport. AZE at doses up to 300 mg/kg, p.o. did not affect urine volume, urinary electrolyte excretion, blood glucose and prothrombin time. These results suggest that AZE at anti-ulcer doses of 10-100 mg/kg, p.o. does not have noticeable effects on general pharmacological properties, and there is no marked differences as compared with those of GAS.
We examined the healing promoting effects of azuletil sodium on acetic acid and clamping cortisone-induced gastric ulcer in rats. For the experiments on clamping-cortisone gastric ulcer, we used not only conventional rats in conventional conditions but also specific pathogen free (SPF) rats on SPF environment in order to prevent infection. The following results were obtained. 1) In acetic acid ulcer, azuletil sodium (AZE) (greater than or equal to 90 mg/kg/day, p.o.) significantly decreased ulcer index. As estimated on the basis of stage analysis (Ulcer, Healing, Scar), AZE (greater than or equal to 30 mg/kg/day, p.o.) significantly promoted the healing of ulcers. 2) In clamping cortisone ulcer (conventional), AZE (100 mg/kg/day, p.o.) significantly promoted the regeneration of blood vessels. 3) In clamping cortisone ulcer (SPF), AZE at greater than or equal to 30 mg/kg/day and 100 mg/kg/day significantly increased the healing index and mucosal regeneration index, respectively. 4) In clamping cortisone ulcer (SPF), the infection that was observed in the conventional test was not seen at all and the acceleration of healing was observed. Furthermore, the extent of adhesion was also reduced, and the standard errors of various healing indices were smaller. From these results, it is concluded that AZE accelerated the healing of experimentally-induced gastric ulcers in rats.
Effects of intragastric application of azuletil sodium (KT1-32), a novel antiulcer drug, on transmucosal potential difference (PD) and acid secretion were investigated in the rat stomach. The stomach was mounted on a Lucite chamber and perfused with saline before and after exposure to KT1-32 for 10 min. KT1-32 (3-30 mg/kg) produced an elevation of PD in a dose-dependent manner with a rise of the luminal pH. The increased PD response caused by KT1-32 (10 mg/kg) persisted after removal of the agent from the stomach, but this PD generating effect was significantly mitigated by pretreatment with omeprazole (60 mg/kg, i.p.). KT1-32 raised PD under basal conditions, but did not significantly affect the reduced PD response caused by 30% ethanol. In addition, topical application of KT1-32 significantly reduced acid secretion caused by histamine (4 mg/kg/hr, i.v.) and carbachol (20 micrograms/kg/hr, i.v.). In the in vitro study, KT1-32 at 3.9 x 10(-4) M showed 50% inhibition of the H/K ATPase activity prepared from the hog gastric mucosa. These results suggest that KT1-32 exerts locally antisecretory and PD generating effects. The latter may be accounted for by the antisecretory action, which is probably related to the H/K ATPase inhibition.
In the search for a new class of bone-sparing agents, we have conducted random screening of the domestic chemical library using 45Ca release assay from prelabeled cultured neonatal mouse calvariae and identified a novel synthetic triazolotriazepine JTT-606 as a candidate for a potent inhibitor of bone resorption. JTT-606 inhibited 45Ca release dose dependently not only in the control calvarial culture but also in the stimulated cultures by interleukin-1alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), and parathyroid hormone (PTH). JTT-606 also inhibited both basal and stimulated osteoclast-like (OCL) cell formation in the coculture of mouse osteoblastic cells and bone marrow cells dose dependently, indicating its inhibitory effect on osteoclast differentiation. Ex vivo OCL cell formation by cultured bone marrow cells collected from ovariectomized (OVX) mice also was decreased dose dependently by in vivo application of JTT-606 to a level similar to that from sham-operated mice. Furthermore, JTT-606 inhibited resorbed pit formation by isolated mature osteoclasts as well as by unfractionated bone cells derived from rabbit long bones in the control and FGF-2-stimulated cultures dose dependently, indicating both the direct and the indirect actions of JTT-606 on mature osteoclast function. In addition, JTT-606 reduced production of IL-1alpha, tumor necrosis factor alpha (TNF-alpha), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human peripheral blood mononuclear cell culture. In vivo analyses of mature OVX rats revealed that the application of JTT-606 for 12 weeks increased the BMD of the lumbar spine and decreased the levels of serum osteocalcin and urine deoxypyridinoline to levels similar to those of 17beta-estradiol-treated OVX rats. We propose that JTT-606 may inhibit both osteoclast differentiation and function by down-regulating both the action and the production of bone resorptive factors. It is speculated that JTT-606 could be a potent agent for the treatment of osteopenic disorders with elevated osteoclastic bone resorption.