Phase I trial and pharmacokinetic study of intravenous and oral α-Difluoromethylornithine

Eflornithine-HCl (-difluoromethylornithine or DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity in cell culture and animal tumor models. This phase I study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. Twenty-four patients were entered into this study: 8 received intravenous pulse drug, 10 intravenous continuous infusion of drug, and 6 oral DFMO. The most frequent toxicity was nausea and vomiting which occurred in 9 courses of oral drug. Only two patients receiving intravenous DFMO had nausea and vomiting. Clinically significant thrombocytopenia and audiometric abnormalities were not encountered in contrast to previous experience with 28-day courses of oral DFMO. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/M² every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing.Presented in part at the 20th Annual Meeting of the American Society of Clinical Oncology, May 1984, Toronto, Ontario, Canada     

Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.     

Suppression of tumor growth by a new glycosaminoglycan isolated from the African giant snail Achatina fulica

Acharan sulfate is a new type of glycosaminoglycan from the giant African snail, Achatina fulica. Acharan sulfate, which has a primary repeating disaccharide structure of alpha-D-N-acetylglucosaminyl-2-O-sulfo-alpha-L-iduronic acid, was studied as a potential antitumor agent in both in vivo and in vitro assays. The antiangiogenic activity of acharan sulfate was evaluated in the chorioallantoic membrane assay and by measuring its effect on the proliferation of calf pulmonary artery endothelial cells. In vivo, a matrigel plug assay showed that acharan sulfate suppressed basic fibroblast growth factor (bFGF)-stimulated angiogenesis and lowered the hemoglobin (Hb) content inside the plug. Acharan sulfate was administered s.c. at two doses for 15 days to C57BL/6 mice implanted with murine Lewis lung carcinoma in the back. It was also administered i.p. to ICR mice bearing sarcoma 180 at a dose of 30 mg/kg. Subcutaneous injection of acharan sulfate at doses of 10 and 30 mg/kg decreased tumor weight and tumor volume by 40% without toxicity or resistance. Intraperitoneal injection of acharan sulfate also decreased tumor weight and volume by 40% in sarcoma 180-bearing mice. These results suggest that the antitumor activity of acharan sulfate may be related to the inhibition of angiogenesis.     

A comparative pharmacology study between the intracolonic and oral routes of 5-FU administration in a colon cancer-bearing Yoshida sarcoma rat model

We prepared a colon cancer-bearing Yoshida sarcoma rat model to examine the dose-response relationship of antitumor activity of intracolonically or orally administered 5-fluorouracil (5-FU; 45, 30, 20, 13, and 8 mg/kg). At doses of > or =20 mg/kg and > or =30 mg/kg, the 5-FU intracolonic and oral administration groups each showed a statistically significant difference in antitumor activity against the control group (P<0.05, Williams' test). A statistically significant dose-response relationship was noted in the two routes of administration, with an ED(50) value of 29 mg/kg. White blood cell count tended to decrease at high doses when 5-FU was administered intracolonically and showed a statistically significant decrease at doses of > or =30 mg/kg when 5-FU was administered orally. Regarding the time-course of body weight, even the 5-FU highest dose (45 mg/kg) intracolonic administration group showed no inhibited body weight increase compared to the control group. However, the 5-FU (> or =20 mg/kg) oral administration groups showed a statistically significant difference in body weight increase against the control group. These facts suggested that the intracolonic administration of 5-FU, while exhibiting more potent antitumor activity than that observed in oral administration, allows an extensive reduction in its toxicities compared to oral administration.     

Lack of specific effects of selective D(1) and D(2) dopamine antagonists vs. risperidone on morphine-induced hyperactivity

In the present study, three different dopamine antagonists were challenged in order to counteract hyperactivity induced by 50 mg/kg of morphine. A wide range of doses of morphine (50, 25, 12.5, 6.25, or 3.12 mg/kg) were evaluated on spontaneous locomotor activity. A significant increase was observed only with the two higher doses tested (25 and 50 mg/kg). No decrease was found with any of the doses used at any period of time. After analyzing doses of SCH 23390 (0.5, 0.1, and 0.05 mg/kg), raclopride (0.5, 0.25, and 0.125 mg/kg) and risperidone (0.1, 0.05, and 0.025 mg/kg) administered alone, only the 0.5 mg/kg dose of SCH 23390 decreased locomotor activity. The three compounds counteracted morphine-induced hyperactivity, but with SCH 23390 it was only achieved with the dose of 0.5 mg/kg, which also decreased spontaneous locomotor activity and induced catalepsy. On the other hand, raclopride and risperidone neutralized morphine-induced hyperactivity at doses that did not affect locomotor activity, although the former induced catalepsy when administered with morphine. It is concluded that although the blockade of D(1) and D(2) DA receptors decreases morphine-induced hyperactivity, this action is not specific, contrary to the action of risperidone, which counteracts this hyperactivity without any other motor effects.     

Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice

The anticancer effect of hydroalcoholic extract of Aegle marmelos (AME) was studied in the Ehrlich ascites carcinoma bearing Swiss albino mice. The spatial effect of various AME administration schedules showed that six-day administration increased the survival of tumor bearing mice. The best antineoplastic action of AME was obtained when AME administered through intraperitoneal route than the oral route at equimolar dose. Administration of AME once daily for six consecutive days to the tumor bearing mice caused a dose dependent remission of the tumor at 400 mg/kg body weight, where the greatest antitumor effect was observed and the higher doses showed toxic manifestations. A 24-d lengthening in life span was observed in EAC animals treated with 400 mg/kg AME. This dose of 400 mg/kg was considered as the best dose, where the animals survived up to 43 d post-tumor-cell inoculation as against no survivors in the saline treated control group. The antitumor activity when tested for different schedules for triple administrations, the best effect was observed for 1-2-3, followed by 1-3-5 and 1-5-9 days, respectively. Stage specific evaluation of AME inhibited the increase in body weight gain in animals due to tumor development during early stages only. The AME treatment resulted in a dose dependent elevation in the median survival time (MST) and average survival time (AST) up to 400 mg/kg AME and decline thereafter. The effective dose of 400 mg of AME is 1/6th of the LD50 dose, which increased the MST and AST up to 29 and 27 d, respectively. The acute toxicity study of AME showed that the drug was non-toxic up to a dose of 1750 mg/kg b. wt. The LD10 and LD50 was found to be 2000 and 2250 mg/kg.     

Preclinical evaluation of hematopoietic toxicity of antileukemic agent, 5-aza-2'-deoxycytidine

The hematopoietic toxicity of 5-aza-2'-deoxycytidine (5-AZA-CdR), an experimental antileukemic agent, was investigated in mice and dogs. Mice were administered a 12 h intravenous infusion of 5-AZA-CdR at a total dose of 20 mg/kg and at different times after treatment samples of bone marrow were analyzed for cell count, DNA synthesis and colony-forming activity (CFUc). The 5-AZA-CdR treatment produced a marked decrease in femur cell count and CFUc activity with recovery occurring on days 8-14. DNA synthesis activity increased significantly during the recovery period. Dogs were also administered a 12 h intravenous infusion at doses 3-7 mg/kg and the blood hemogram evaluated. This treatment produced a pronounced leukopenia, granulocytopenia and thrombocytopenia with a nadir between days 7-16 with recovery occurring on days 19-21. These results indicate that 5-AZA-CdR produces marked hematopoietic toxicity in mice and dogs and this toxicity appears to be reversible under these experimental conditions.     

Comparative studies on antitumor activity of Klebsiella O3 lipopolysaccharide and its polysaccharide fraction in mice

The antitumor activity of the polysaccharide fraction (OPS) obtained by the acid hydrolysis of Klebsiella O3 lipopolysaccharide (KO3 LPS) isolated from the culture supernatant of the decapsulated mutant strain LEN-1 (03: K1-) against both allogeneic tumor and syngeneic tumor systems in mice was compared with that of KO3 LPS. OPS prolonged the life span of MM2-bearing C3H/He mice by intraperitoneal (i.p.) pre- and post-treatment at the doses of 100 and 1000 mg/kg. However, large amounts of OPS were needed to show the antitumor activity as compared with KO3 LPS. OPS showed no growth inhibitory activity against Meth-A sarcoma in BALB/c mice by i.p., intravenous (i.v.) or intratumoral (i.t.) administration. When 1000 mg/kg of OPS was i.p. administered once a day for 10 days, OPS significantly inhibited the tumor growth of Sarcoma-180 solid type tumor. On the other hand, KO3 LPS significantly suppressed the growth of Meth-A tumor by i.t. administration at the doses of 0.3 and 1.0 mg/kg and showed complete regression in 8 and 9 out of 10 mice, respectively. In MM2 tumor, KO3 LPS also showed complete regression in all mice post-treated by i.p. administration at the dose of 1.0 mg/kg. These results suggest that OPS has antitumor activity on the tumors used in this study, but the activity was less than that of KO3 LPS.     

Treatment schedule dependency of antitumor effect of deoxyspergualin

The effect of treatment schedule on antitumor activity of 15-deoxyspergualin (NKT-01) against P388 leukemia was studied by changing each 2 out of 3 factors of administration schedule (number of injections, injection interval, and injection period) with the rest being constant. The antitumor activity of NKT-01 was shown to be strongly time-dependent; higher efficacy was obtained with prolongation of treatment period and with increasing the number of injections. The dosing interval seemed not to be a dominant factor regarding the activity of NKT-01. The strong dependency on treatment period was also observed in continuous infusion schedules by using Alzet 2001 osmotic minipump. The degree of dependency on infusion period was estimated to be 3- to 4-fold stronger than that on the infused dose by logarithmical plotting of the infusion periods and infused daily doses required to produce 130% of T/C(%). The effective dose range by the continuous infusion was slightly narrower than that by the repeated bolus injections, although slightly higher maximal activity was obtained at the optimal dose. Hyperacute pharmacological toxicity caused by bolus injection of high dose (51.2 mg/kg) of NKT-01 did not occur by continuous infusion method even at much higher dose (409.6 mg/kg/day). Cumulative gastrointestinal toxicity was observed by prolonged continuous infusion as well as repetitive treatment schedule. From these results on antitumor activity and toxicity by various treatment schedules, recommendable clinical modality for NKT-01 seems to be the short-time infusion on every or every other day continuing for a few weeks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of di(2-ethylhexyl)phthalate on 17 beta-hydroxysteroid dehydrogenase activity in testis of rat.

The purpose of the present study was to demonstrate the effects of di(2-ethylhexyl)phthalate (DEHP) on 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity in the testis of adult rat. DEHP was administered to rats by gavage at doses of 250, 500, 1000 and 2000 mg/kg body wt./d for 15 days. The absolute and relative weights of testes were significantly decreased only at the highest dose level. The activity of 17 beta-HSD was decreased in animals exposed to 1000 and 2000 mg/kg of DEHP. The data suggest that DEHP may affect testicular steroidogenesis adversely.     

Cefepime (diHCl/L-arginine blend): intravenous continuous infusion and/or single dose subcutaneous toxicity study in rats and dogs]

To investigate single dose toxicity of cefepime (CFPM diHCl/L-arginine blend), the test drug was administered to rats [Crj: CD (SD)] of both sexes at dose levels of 500, 1,000 and 2,000 mg/kg using intravenous continuous infusion or subcutaneous injection, and to male beagle dogs at 1,000 and 2,000 mg/kg using intravenous continuous infusion. As the control, two additional groups of each animals were given either saline or L-arginine alone which was used in the test formulation to adjust pH values of CFPM diHCl solutions. The obtained results are summarized as follows: 1. Rats dosed with 2,000 mg/kg CFPM through intravenous continuous infusion showed slightly decreased spontaneous physical activity. One male rat dosed with L-arginine alone via continuous infusion also showed slightly decreased activity. Slight to severe inflammatory reactions at injection sites including sloughing of the tail were prominent at doses of 1,000 or 2,000 mg/kg of CFPM, or L-arginine alone. Average body weights of rats in the test groups of either sex were comparable to the controls in all of the dose groups of the same sex during the 14-day test period. 2. Rats receiving 2,000 mg/kg CFPM in single subcutaneous injection showed slightly diminished activities. Slight to moderate reactions occurred around the injection site (viz., hardening, depilation, scab-formation and necrosis) in rats injected any of the 3 doses of CFPM. Though body weight gains were slightly retarded in male rats receiving 2,000 mg/kg CFPM during the last half of the observation period, such weight gain retardation was not observed in rats of other dose groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

关于抗肿瘤药物的研究 Ⅴ.一些抗肿瘤药物合并应用的研究

作者对一些抗肿瘤药物的合并应用,做了一些实驗,得到以下的結果:(1)己烯雌酚磷酰胺(F₂₂₀₂)与6-巯基嘌呤(6-MP)的合并应用,增加了药物对小白鼠肉瘤180及大白鼠Jensen肉瘤生长的抑制作用。(2)thiocit能降低氮芥对小白鼠及大白鼠的毒性,但同时也降低了氮芥的抗肿瘤作用。(3)半胱氨酸不能对抗6-巯基嘌呤对小白鼠死亡毒性,但却能保护大白鼠白血細胞不受6-巯基嘌呤的影响。     

Metabolism of ifosfamide to chloroacetaldehyde contributes to antitumor activity in vivo.

Metabolic activation of ifosfamide (IFO) leads to the active 4-hydroxy-metabolite and to a substantial liberation of chloroacetaldehyde (CAA). CAA has been presumed responsible for side effects of IFO. We recently have shown cytotoxic effects of CAA against human tumor cells in vitro. The aim of this study was to demonstrate antitumor effects of CAA in vivo, and to compare its potency to 4-OH-IFO. Pharmacokinetics of IFO and metabolites were evaluated after infusion of 250 mg/kg IFO in mice. The area under the curve (AUC) for 4-hydroxyifosfamide (4-OH-IFO) and CAA were 138. 5 and 102.4 micromol. h/liter, respectively. To compare pharmacokinetics and antitumor effects, the mice received isolated infusion of 4-OH-IFO or CAA in equimolar doses to IFO. Administration of 4-OH-IFO yielded AUC values comparable with those obtained after administration of the parent drug. In contrast, infusion of isolated CAA via tail vein gave a low AUC value of 51.5 micromol. h/liter due to slow flow in the tail vein and rapid degradation. Administration of the parent drug gave highly cytotoxic intratumoral peak concentrations of 25 and 12 micromol/kg tumor weight for 4-OH-IFO and CAA in MX1 xenotransplanted nude mice. Both IFO and isolated 4-OH-IFO led to complete remissions. Administration of isolated CAA (75 mg/kg) delayed tumor growth significantly. The equitoxic dose of isolated 4-OH-IFO was 40 mg/kg. On a molar basis CAA was seven times less potent as 4-OH-IFO. However, on the basis of achieved AUC values, CAA seems to exhibit a similar antitumor activity to 4-OH-IFO.     

Antitumor activity of 2-amino-4,4alpha-dihydro-4alpha, 7-dimethyl-3H-phenoxazine-3-one against Meth A tumor transplanted into BALB/c mice

We examined the in vivo effect of 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3- one (Phx) on Meth A carcinoma cells transplanted into BALB/c mice, in terms of both antitumor activity and side effects. Phx, which was synthesized by the reaction of 2-amino-5-methylphenol with bovine hemolysates, was administered i.p. at doses of 1 and 5 mg/kg to BALB/c mice transplanted with Meth A tumor cells. Phx exerted a strong antitumor activity to Meth A tumor growing in the mice as 5-fluorouracil (5-FU) did. The antitumor activity of Phx at the dose of 5 mg/kg was comparable to that of 5-FU at the dose of 7.8 mg/kg. In contrast, unlike 5-FU, Phx did not cause leukopenia while showing a strong antitumor activity. The compound also produced little changes in body weight and no wasting of mice developed. These results show that Phx has strong anti-tumor activity, but exerts lower side effects and suggest that Phx is available for therapeutic purposes in the future.     

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).     

Effect of citral on mouse hepatic cytochrome P450 enzymes

Context: Citral is used as a potential natural treatment for various infectious diseases.

Objective: To examine the effect of citral on the mRNA expression and activities of cytochrome P450 (CYP450) enzymes and establish the relationship between citral-induced liver injury and oxidative stress.

Materials and methods: ICR mice were randomly divided into citral (20, 200, and 2000?mg/kglow), Tween-80, and control groups (0.9% saline), 10 mice in each group. The citral-treated groups were intragastrically administered citral for 3 d, control groups treated with 0.5% Tween-80 and 0.9% saline in the same way. Liver injury and CYP450 enzymes were analyzed by analyzing the histopathological changes and the changes of related enzymes.

Results: Citral treatment (2000?mg/kg) for 3 d increased serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels, as well as glutathione, gydroxyl radicals, malonaldehyde and total superoxide dismutase contents, but decreased the content of total antioxidant capacity. In doses of 20 and 200?mg/kg groups mice, the contents of NO were decreased significantly and other changes were similar to the 2000?mg/kg group mice, but the liver damage was most severe in the 2000?mg/kg group. Citral induced the mRNA expression and activities of CYP450 1A2, 2D22, and 2E1 in the liver of mice at doses of 20 and 200?mg/kg. There were no changes in testing indexes in Tween-80 treated group mice. Due to its toxic effects, the CYP induction effect of citral negatively correlated with its dose. Although the mRNA expression of CYP450 3A11 was induced by citral, its activity was not affected by low and moderate doses of citral. CYP450 3A11 activity was significantly decreased by high-dose citral.

Conclusions: Citral is hepatotoxic and induced oxidative stress in higher dose, which has a negative effect on CYP450 enzymes. These data suggest caution needs to be taken in order to avoid citral-drug interactions in human beings.     

西咪替丁对长春瑞滨所致输液性静脉炎的防治作用

目的：观察长春瑞滨（VIN）不同给药方案致输液性静脉炎的作用,以及西咪替丁（CI M）对VIN所致静脉炎的干预效果。方法：在使用CI M1.5 mg/鼠干预的情况下,分别采用不同剂量（18.75、28.13、37.50、56.25和75.00 mg/kg）,不同给药速度（0.15、0.30和0.75μL/s）以及不同浓度（10、5和2.5 mg/mL）,向c57小鼠尾静脉注射VIN诱导静脉炎。给药后每天观察静脉炎发生状况和消退情况。结果：随着VIN剂量的增加,小鼠静脉炎的发生率逐渐增加。VIN给药速度越慢,在一定限度内静脉炎的发生率越低;推注过快,可导致小鼠猝死。提前30 min给予CI M1.5 mg可以预防VIN所致静脉炎的发生。结论：CIM在适宜的给药方案下可以预防VIN所致输液性静脉炎的发生。     

Antagonism of amphetamine locomotor stimulation in rats by single doses of marijuana extract administered orally

The influence of marijuana extract distillate on (+)-amphetamine stimulation of locomotor activity was examined in rats. Marijuana was administered orally and amphetamine was injected intraperitoneally. In rats acclimated to the activity cages, doses of the extract of 5, 10, and 20 mg/kg Δ⁹-THC administered one hour before amphetamine resulted in a significant antagonism of the locomotor stimulation induced by 1 mg/kg (+)-amphetamine; doses of 0·625, 1·25 and 2·5 mg/kg Δ⁹-THC had no effect on the amphetamine response. A dose of 10 mg/kg Δ⁹-THC (as the extract) antagonized the stimulation produced by 0·5,1 and 2 mg/kg (+)-amphetamine in acclimated animals without depressing baseline activity; however, the same dose of marijuana failed to alter significantly the stimulant effect of 1 mg/kg (+)-amphetamine in nonacclimated rats. Although pretreatment with marijuana extract 1 hr before injection of amphetamine resulted in a marked depression of the amphetamine response, when both drugs were administered at the same time only a small and non-significant decrement in the amphetamine response was observed. In conclusion, this study clearly demonstrates that orally administered marijuana antagonizes amphetamine-induced locomotor stimulation in the rat. Mo evidence of enhancement of the amphetamine effect was observed.     

Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion

BACKGROUND: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethylamino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. PATIENTS AND METHODS: 45 patients (7 female, 38 male; median age 54 [range 37-73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. RESULTS: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2gamma) was 14.7 +/- 3.7 h. The AUC at 250 mg/m2 was determined to be 330 +/- 147 microg/mlh, the plasma clearance of NK611 was 16.2 +/- 8.2 ml/min x m2 and the V(ss) was 16.8 +/- 3.3 l/m2. Protein binding of NK611 was 98.7%. CONCLUSION: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.     

Alleviation of intestinal lesions by combined treatment with a 5-fluoro-2'-deoxyuridine (FUDR) derivative and alpha-difluoromethylornithine (DFMO)[correction of DMFO] in tumor-bearing mice.

alpha-Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, reduced intestinal lesions in tumor-bearing mice caused by treatment with N3-(3-methylbenzoyl)-3',5'-diacetyl [corrected]-FUDR (FF-705), a derivative of 5-fluoro-2'-deoxyuridine (FUDR). FF-705 at 32 mg/kg (the effective dose) suppressed tumor growth to about 40% of the control level. At this dose, body weight gain was suppressed slightly when FF-705 was given alone, and this change was milder in the DFMO-supplemented group. Intestinal lesions were suppressed almost completely by concomitant treatment with DFMO. The gross lesion index in the combined treatment group was similar to that in the controls and significantly smaller than in the FF-705-alone group (0.3 and 1.9, respectively). The histological lesion index in the combined treatment group was also significantly smaller than in the FF-705-alone group (7.9 and 23.8, respectively). When FF-705 was given at 64 mg/kg, the intestinal mucosal lesions were more severe, but DFMO supplementation reduced them by approximately 50%. Moreover, maltase and diamine oxidase activities of intestinal epithelium remained higher with combined treatment than with FF-705 alone. With FF-705 at 256 mg/kg (a toxic dose), DFMO had little protective effect against intestinal damage.