Biomedical subjects

M Tsutsumi

Publications and source records attributed to M Tsutsumi.

At least 19 recordsLinked to original sources

PubMed2000

Absence of p16, p21 and p53 gene alterations in hepatocellular carcinomas induced by N-nitrosodiethylamine or a choline-deficient L-amino acid-defined diet in rats.

To clarify the involvement of tumor suppressor genes in exogenous and endogenous liver carcinogenesis, alterations of p16, p21 and p53 in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and a choline deficient L-amino acid-defined (CDAA) diet in rats were investigated. Male Fischer 344 rats received DEN at 6-week of age followed by partial hepatectomy (PH), with colchicine to induce cell cycle disturbance, and a selection pressure regimen. Sacrifice was after 42 weeks. Other animals continuously received a CDAA diet for 75 weeks and were then killed. Eleven and 15 HCCs were obtained, respectively. Total RNA was extracted from and cDNA was synthesized with reverse transcriptase to allow investigation of mutations in p16, p21 and p53 by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analysis. Expression of p16 and p21 mRNA was also analyzed by reverse transcription (RT)-PCR. The results showed no mutations or deletions of p16, p21 and p53 in any of the HCCs induced by DEN or CDAA. Loss or decrease of p16 and p21 expression were also not found, suggesting that p16, p21 and p53 alteration may not be necessary for either exogenous or endogenous liver carcinogenesis in rats.

Animals↗

PubMed2000

Increased expression of cyclooxygenase-2 protein in rat lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine.

Expression of cyclooxygenase (COX)-2 protein in preneoplastic and neoplastic lung lesions induced by the administration of 2000 ppm of N-nitrosobis(2-hydroxypropyl)amine (BHP) in the drinking water to Wistar male rats, was examined immunohistochemically. The majority of alveolar/bronchiolar adenomas (ADs) and all adenocarcinomas (ADCs) examined, stained positive or strongly positive for COX-2. In contrast, only a minority of alveolar/bronchiolar hyperplasias demonstrated immunoreactivity and half of the squamous cell carcinomas examined, were only weakly positive. Western blotting analysis also revealed expression of COX-2 protein in the resected ADs and ADCs. These results clearly indicate up-regulated expression of COX-2 in lung neoplastic lesions, particularly ADs and ADCs, induced by BHP in rats.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2000

The response of Parp knockout mice against DNA damaging agents.

Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have identified the various roles of Parp in cellular responses to DNA damage. The partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant mice indicates the participation of Parp in the repair of DNA strand break. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage induced by reactive oxygen species implicates the contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to the lethal effects of gamma-irradiation. Parp(-/-) mice show more severe villous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(-/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the glandular stomach and other tissues, such as the testes, after gamma-irradiation. Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the spleen is probably the underlying mechanism of hemorrhagic tendency in various tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity could contribute to post-irradiation tissue hemorrhage.

Alkylating Agents↗

PubMed2000

Age and organ dependent spontaneous generation of nuclear 8-hydroxydeoxyguanosine in male Fischer 344 rats.

8-Hydroxydeoxyguanosine (8-OHdG) is a major oxidative DNA adduct playing roles in senescence, carcinogenesis and various disease processes. High-performance liquid chromatography with an electrochemical detection (HPLC-ECD) method has been widely used to assess organ levels of 8-OHdG, and a recently introduced immunohistochemical approach has made it possible to clarify intra-organ localization. In the present study, these methods were employed to reveal age-dependent changes in nuclear 8-OHdG within various tissues of male Fischer 344 rats between 18 fetal days and 104 weeks of age. 8-OHdG was detected in the nuclei of cerebellar small granule and small cortical cells, cerebral nerve cells, and choroid plexus epithelia of the brain and ependymal cells of the spinal cord; parenchymal cells in the anterior lobe of the pituitary and adrenal glands (mainly cortex); bronchial epithelium of the lung; intra-hepatic bile duct, pancreatic duct, glandular gastric and intestinal epithelial cells; renal tubular epithelial cells (mainly medulla); and spermatogonia and spermatocytes of the testis and seminal vesicle epithelia. The nuclear 8-OHdG levels were high (more than two lesions per 10(6) deoxyguanosines) from 7 days to 104 weeks of age in the brain, 3 to 6 weeks in the adrenal gland, 6 to 104 weeks in the lung, and 3 to 52 weeks in the testis. In the other organs, the nuclear 8-OHdG levels remained low throughout. These findings provide a basis for research dealing with oxidative stress by indicating organ-specific and age- but not aging-dependent changes in the localization of spontaneously generated nuclear 8-OHdG in intact rats. The immunohistochemical approach has advantages for assessing variation of 8-OHdG formation at the cellular level not accessible to the HPLC-ECD method.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Inhibitory effects of combined administration of antibiotics and anti-inflammatory drugs on lung tumor development initiated by N-nitrosobis(2-hydroxypropyl)amine in rats.

The effects of antibiotics and anti-inflammatory drugs on the promotion stage of lung carcinogenesis initiated with N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats were investigated in two experiments with a similar protocol. In experiment 1, rats received tap water containing 2000 p.p.m. BHP for 12 weeks followed by basal diet or basal diet containing 0.02% erythromycin (EM), 0. 04% ampicillin (ABPC), 1.5% sho-saiko-to, 0.02% EM plus 1.5% sho-saiko-to or 0.04% ABPC plus 1.5% sho-saiko-to for 8 weeks after BHP administration. The development of adenocarcinomas (AC), squamous cell carcinomas (SqC) and adenosquamous carcinomas (ASqC) was completely inhibited in rats given ABPC plus sho-saiko-to and the numbers of lung lesions including alveolar hyperplasias, adenomas and carcinomas were decreased in rats given EM plus sho-saiko-to or ABPC plus sho-saiko-to. Neutrophil and macrophage infiltration into alveolar spaces of the lung were also markedly suppressed. In experiment 2, rats received BHP in the same manner as in experiment 1 and basal diet or basal diet containing 0.04% ABPC, 0.006% piroxicam, 0.04% ABPC plus 0.006% piroxicam and 0.04% ABPC plus 0.75% ougon for 8 weeks. The incidence and number of carcinomas, including ACs, SqCs and ASqCs were decreased in rats given ABPC plus piroxicam or ABPC plus ougon. Bacteria, mainly Escherichia coli, were detected in broncho-alveolar lavage of rats receiving BHP. The results suggest that chronic inflammation might be involved in the progression of lung carcinogenesis by BHP in rats and its suppression may therefore be useful as a chemopreventive strategy in lung cancer clinics.

Adenocarcinoma↗

PubMed2000

Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates.

Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100 mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth and continuing for up to 24 years. Malignant tumors were diagnosed in three 24-year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg). Benign tumors were found at necropsy in three females; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclamate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) at various germ cell levels mixed with normal spermatogenesis was observed in both the cyclamate-treated and the control monkeys, all of which were over 20 years old. Measurements of terminal cyclohexylamine concentrations showed that three of the males dosed with cyclamate at 500 mg/kg were high converters, with plasma concentrations comparable to the levels that produce testicular atrophy in rats. However, only one of the three high converters showed histologic evidence of irregular spermatogenesis. The overall conclusion is that the testicular abnormalities and the sporadic cases of different malignancies found after more than 20 years of dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys.

Animals↗

PubMed2000

Lack of involvement of metallothionein expression in pancreatic carcinogenesis by N-nitrosobis (2-oxopropyl) amine in Syrian hamsters.

The possible involvement of metallothionein (MT) in pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl) amine (BOP) in hamsters was investigated. Hamsters received subcutaneous (s.c.) injections with dissolved BOP to 70 mg/kg body weight (BW) followed 7 days later by 20 mg/kg BW BOP and they were sacrificed at 4, 11, 16 and 27 weeks after the beginning of the experiment. MT expression was studied by immunohistochemistry and MT contents were assayed biochemically. Pancreatic ductal hyperplasias were developed from 11 weeks on and carcinomas from 16 weeks on, the incidence of the latter reaching 73% at the end of experiment. However, while normal appearing proliferating duct cells were sometimes positive, MT expression was not evident in hyperplasia (H), atypical hyperplasia (AH) or carcinoma (C), and MT contents did not significantly differ in pancreas of hamsters receiving saline or BOP at any time point. The results suggest that MT is not involved in pancreatic duct carcinogenesis. However, the presence of MT in proliferating ducts not related to carcinogenesis may suggest some unknown role for MT in cellular homeostasis.

Animals↗

PubMed2000

Study of mitochondrial DNA deletion in alcoholics.

BACKGROUND: Recently, it has been reported that single or multiple mitochondrial DNA (Mt-DNA) deletions have been observed frequently in liver tissue and white blood cells (WBC) obtained from patients with alcoholic liver disease (ALD). In this study, we investigated the deletion of the Mt-DNA encoding adenosine triphosphatase (ATPase) region in WBC to clarify whether Mt-DNA heteroplasmy caused by alcohol drinking is reversible. METHODS: Blood samples were obtained from 4 healthy volunteers, 56 patients with ALD, and 106 nonalcoholic healthy controls. The Mt-DNA encoded ATPase region was amplified by polymerase chain reaction (PCR) by using two primers: forward primer, 5'-AACCAACACCTCTTACAGTGA; and reverse primer; 5'-TTGGTGGGTCATTATGTGTTGT. RESULTS: Heteroplasmy was observed in one volunteer on day 3 and in the remaining persons on day 4 after the start of alcohol consumption. Heteroplasmy was observed for another 6 days after alcohol consumption stopped, but on the 7th day it had disappeared in all volunteers. In WBC Mt-DNA obtained from ALD patients within 3 days of abstinence, heteroplasmy was observed in 38 of the 56 patients (67.9%), whereas heteroplasmy was not detected in any healthy subjects. In 10 of the 18 ALD patients (56%) who had heteroplasmy within 3 days of abstinence, heteroplasmy disappeared after 4 weeks of abstinence. CONCLUSION: An acquired mutation of Mt-DNA, at least in the encoding ATPase region, may result from alcohol drinking and may be reversed by stopping drinking.

Adenosine Triphosphatases↗

PubMed2000

Immunohistochemical study of hyaluronate receptor (CD44) in alcoholic liver disease.

BACKGROUND: It has been suggested that the elevation of serum hyaluronate (HA) levels in liver diseases may be due to increased synthesis of HA by hepatic stellate cells or decreased degradation by sinusoidal endothelial cells. The increase in serum HA levels in patients with cirrhosis is thought to be a response to a reduction in HA receptors (CD44) in hepatic sinusoidal endothelial cells. To learn more about how alcohol affects the number and distribution of HA receptors of hepatic sinusoidal endothelial cells, we immunohistochemically studied CD44 levels in liver biopsy obtained from patients with alcoholic liver disease (ALD patients) and also from patients with nonalcoholic liver disease (non-ALD); ALD patients were evaluated when they were currently drinking and again after they became abstinent. Normal liver tissue obtained from three autopsy cases served as a control. METHODS: Liver biopsy specimens were obtained from 18 ALD patients and 12 non-ALD patients. In ALD patients, liver biopsy was performed twice within 3 days and 4 to 8 weeks after abstinence when serum levels of aspartate aminotransferase and alanine aminotransferase became normal. CD44 in liver specimens was stained with anti-CD44 antibody by streptavidine-biotin-peroxidase complex. The intensity of the staining of CD44 in liver tissue was determined by a computer-assisted imaging analyzer. We also measured serum levels of CD44 in both ALD and non-ALD patients. RESULTS: The intensity and the number of CD44 staining increased in both ALD and non-ALD patients compared with those in normal liver, which was negative. The staining intensity of CD44 in liver specimens obtained from patients with ALD who were active in alcohol consumption were significantly higher when compared with patients with ALD after abstinence. Serum levels of CD44 in patients with liver disease increased compared with those of healthy subjects. CONCLUSIONS: The results suggest that HA receptors may increase to degrade the increased HA in serum and/or liver.

Aged↗

PubMed2000

A novel mutation of KCNQ3 (c.925T-->C) in a Japanese family with benign familial neonatal convulsions.

At present, only one mutation of KCNQ3, a KCNQ potassium channel gene, has been identified as a cause of benign familial neonatal convulsions type 2 (BFNC2). We found a T to C substitution (c.925T-C) on one allele of affected individuals in a Japanese family with BFNC but not on 200 alleles from healthy subjects. c.925T-->C replaced Trp309, a conserved residue within the P-loop of the KCNQ potassium channel family that holds the channel pore open, with an Arg (W309R). We report c.925T-->C as the second mutation of KCNQ3 responsible for BFNC2.

Amino Acid Sequence↗

PubMed1999

Amino acid sequence of a putative transposase protein of the medaka fish transposable element Tol2 deduced from mRNA nucleotide sequences.

Tol2 is a terminal-inverted repeat transposable element of the medaka fish Oryzias latipes. It is one of a few elements of this class so far demonstrated to be active in vertebrates, thus providing a unique tool for establishing a gene tagging system. For the purpose of identifying its transposase, we analyzed the structures of mRNAs originating from the Tol2 element. The results indicated that transcription of Tol2 is initiated at several sites, the four open reading frames in Tol2 roughly corresponding to exons, and that two main forms of mRNAs, covering exons 1-4 and exons 2-4, are present in medaka fish cells. One or both of these mRNAs are likely to encode a transposase, the amino acid sequence of which was deduced.

Amino Acid Sequence↗

PubMed1999

Carcinogenicity of heterocyclic amines for the pancreatic duct epithelium in hamsters.

Effects of eight heterocyclic amines (HCAs) on pancreatic duct carcinogenesis were investigated in a rapid production model in hamsters. N-Nitrosobis(2-oxopropyl)amine (BOP) was given to effect initiation, followed by augmentation pressure consisting of four daily i.p. injections of 500 mg/kg DL-ethionine, a choline-deficient (CD) diet, a single i.p. injection of 800 mg/kg L-methionine and a s.c. injection of 20 mg/kg BOP. After two cycles of augmentation pressure, the HCAs 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-9H-pyrido[2,3-b]indole (AalphaC), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC) or 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [4,8-DiMeIQx) were administered in the diet for 50 or 70 days. The numbers of pancreatic ductal hyperplasias (H) and a total lesions including, atypical hyperplasia (AH), carcinomas in situ (CIS) and invasive carcinomas, were increased in hamsters given the diet containing 0.02% Trp-P-1 for 50 days. This result was confirmed and extended by the finding of increased numbers of invasive carcinomas in hamsters given 0.02% Trp-P-1 for 70 days. The number and incidence of invasive carcinomas were also elevated in hamsters given the diet containing 0.06% 4,8-DiMeIQx for 50 days. These results suggest a possible involvement of Trp-P-1 and 4,8-DiMeIQx in pancreatic duct carcinogenesis.

Animals↗

PubMed1999

Different frequencies and patterns of beta-catenin mutations in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats.

To allow a study of beta-catenin mutations in hepatocellular carcinomas (HCCs) induced by exogenous and endogenous carcinogens, we induced tumors in male Fischer 344 rats with N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet. Administration of the former was followed by partial hepatectomy with colchicine to induce cell cycle disturbance and a selection pressure regimen (K. Ohashi et al., Cancer Res., 56: 3474-3479, 1996; M. Tsutsumi et al., Jpn. J. Cancer Res., 87: 5-9, 1996). HCCs were obtained after 42 weeks. With continuous choline-deficient L-amino acid-defined feeding, tumors were sampled after 75 weeks. Total RNA was extracted from individual lesions and mutations in the glycogen synthase kinase-3beta phosphorylation consensus motif of beta-catenin were investigated by reverse transcriptase-PCR-single-strand conformation polymorphism analysis followed by nucleotide sequencing. Changes were detected in 5 of 11 HCCs induced by the exogenous carcinogen. The observed shifts of C:G-->G:C or C:G-->A:T at codon 33 and G:C-->T:A transversions at codon 34 were associated with beta-catenin protein accumulation and confirmed by Western blot analysis. Only 2 of 15 HCCs induced in the endogenous carcinogenesis regimen demonstrated mutations, those being transitions of C:G-->T:A at codon 41 without amino acid alteration. These results suggest that different genetic pathways underlie exogenous and endogenous liver carcinogenesis in rats.

Amino Acids↗

PubMed1999

Cloning of differentially expressed genes in highly and low metastatic rat osteosarcomas by a modified cDNA-AFLP method.

To identify differentially expressed genes between highly and low metastatic rat transplantable osteosarcomas, we applied a modified AFLP (amplified fragment length polymorphisms) method for cDNA subtraction. The specific point of our modification is selective amplification using suppression PCR technique after restriction enzyme cutting. Our cDNA-AFLP gave high reproducibility (about 95%) in mRNA patterns and enabled us to clone four dominantly expressed genes in a highly metastatic tumor line. Three showed homology with known genes, encoding Ki-67, a proliferation-associated effective marker of malignancy, type IV collagen alpha-3, a major component of basement membrane, and KIAA77 for which the function is unknown. Although one fragment showed no database homology, we revealed a derivation from the rat homologue of the Drosophila melanogaster diaphanous gene (Dia) by cloning of longer cDNA. Dia genes, known to affect actin filament formation, are downstream effectors of Rho small GTPase. The results suggest that alterations in the expression of cytoskeletal protein, basement membrane elements, and proliferative markers may be important for metastasis of osteosarcomas.

Amino Acid Sequence↗

PubMed1999

Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats.

In the present experiment, the expression of matrix metalloproteinase (MMP)-2 and MMP-9, key proteins in the MMP family, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, antagonistic proteins against MMP-2 and MMP-9, respectively, were investigated by Northern blot analysis in rat transplantable osteosarcomas with high and low metastatic potencies. Two transplantable osteosarcomas, one induced with the carcinogen, 4-hydroxyaminoquinoline 1-oxide (4-HAQO) (COS, chemical carcinogen-induced osteosarcoma), and the other, a spontaneous lesion (SOS, spontaneous osteosarcoma), were repeatedly transplanted from lung nodules to generate lines with high metastatic potency, C-SLM (chemical carcinogen-induced osteosarcoma, selected lung metastatic lesions) and S-SLM (spontaneous osteosarcoma, selected lung metastatic lesions), respectively. MMP-9 was overexpressed in both S-SLM and C-SLM, and TIMP-2 in the case of S-SLM. Neither MMP-2 nor TIMP-1 was overexpressed in either of the transplantable osteosarcomas with high metastatic potentials. The active form MMP-9, studied by zymography, increased in S-SLM and C-SLM but not in SOS and COS. MMP-9 mRNA expression was highly correlated with the gelatinolytic activity of active form MMP-9 (r = 0.85, P < 0.0001) and with the activation ratio of MMP-9 (r = 0.83, P < 0.0001). However, the active form MMP-2 was not detectable in all cases. These results suggest that overexpression of MMP-9 mRNA is one of the essential factors in the acquisition of metastatic potential in rat transplantable osteosarcomas.

4-Hydroxyaminoquinoline-1-oxide↗

PubMed1999

Novel endothelin B receptor transcripts with the potential of generating a new receptor.

Using RT-PCR and rapid amplification of 5' cDNA ends (5' RACE), we have cloned three previously unrecognized endothelin B receptor (EDNRB) transcripts from a human melanoma cell line. Three distinct types of cDNAs (EDNRBDelta1, Delta2 and Delta3) were identified. EDNRBDelta1 starts upstream of the published transcription start site of hEDNRB without splicing, whereas, EDNRBDelta2 and EDNRBDelta3 are alternatively spliced. EDNRBDelta1 and EDNRBDelta2 share the same transcription initiation site and are 560bp upstream of the conventional hEDNRB, whereas that of EDNRBDelta3 is 939bp upstream from that described for the conventional hEDNRB. Interestingly, many transcription factor motifs are detectable in the upstream regions of these transcription initiation sites. The predicted amino acid sequences reveal that EDNRBDelta1 and EDNRBDelta2 produce the same protein as the conventional hEDNRB, but EDNRBDelta3 would give rise to additional in-frame 89- or 83-amino-acid residues at the N-terminus. EDNRBDelta3 generates the same amino acid sequence at the C terminus, but utilizes the polyadenylation signal within the open reading frame, resulting in a shorter 3'UTR. These transcripts are widely expressed in human tissues, but their expression patterns vary between different tissues.

3' Untranslated Regions↗

PubMed1999

Distribution of Tsc2 protein in various normal rat tissues and renal tumours of Tsc2 mutant (Eker) rat detected by immunohistochemistry.

Alterations in the rat tuberous sclerosis gene (Tsc2) are responsible for the hereditary renal carcinomas (RCs) of Eker rat. We examined protein distribution in various normal rat tissues and the Eker RCs by immunohistochemistry. Tsc2 protein is expressed in the mammary ducts, salivary glands, gastric glands, parathyroid, small and large intestine, ovary and uterus. Specific expression of Tsc2 protein is found in the B cells of pancreatic islets and in the smooth muscle of lung veins. Interestingly, in the RCs of Eker rat, Tsc2 protein was detectable with some variation in reactivity.

Animals↗

PubMed1999

Delay in administration of CDDP until completion of AGM-1470 treatment enhances antimetastatic and antitumor effects.

The efficacy of cis-diammine dichloroplatinum (CDDP) therapy in combination with continuous administration of angiogenesis inhibitor o-(chloroacetyl-carbamoyl) fumagillol (AGM-1470) was evaluated experimentally using a transplantable rat osteosarcoma line previously established in our laboratory. AGM-1470 (2.5 mg/kg body weight/week) was administered by Alzet osmotic pumps for 2 weeks starting from 7 days after tumor inplantation and CDDP (1.25 mg/kg) was given on days 21 and 24. The number of lung metastatic nodules was counted and the wet weights of the primary tumors were measured 5 weeks after tumor inplantation. Values with administration of CDDP 3 days after discontinuation of AGM-1470 were significantly lower than when the two agents were coadministered (P < 0.05). This animal model should facilitate optimization of the timing of combination therapy.

Animals↗