Antitumor activity of ME2303, a fluorine-containing anthracycline, against human tumors implanted in nude mice

A fluorine-containing anthracycline, ME2303, given intravenously once a week for 4 weeks at the maximum tolerated doses showed better therapeutic effects against 2 gastric, 3 lung and 2 human breast tumor xenografts than did adriamycin (ADM) at the maximum tolerated dose. Among the tumors, ME2303 showed a better effect against St-40, a well-differentiated human gastric adenocarcinoma, against which ADM showed only a marginal effect. Likewise, ME2303 was more effective against Lu-24 human small cell carcinoma and MX-1 human medullary tubular adenocarcinoma than ADM. Notably, the Lu-24 tumor, developed in nude mice, disappeared after the treatment in 3 out of 6 mice. ME2303 would be an interesting compound for phase I and II clinical studies in the future.     

Antitumor effect of intermittent oral administration of UFT against human rectal cancer xenografted in nude mice

Effect and toxicities of oral administration of UFT were examined with tumor xenografts (COK-7LiM) in nude mice. Special attention was paid to the differences between daily (Q1D X 9) and intermittent (Q4D X 3) treatments with this agent. The optimal doses of UFT were determined on the basis of the maximal tolerated dose of the agent in nude mice. It was remarkable that the chemotherapeutic effect by intermittent administration of UFT showed a significantly better result than that by daily administration. No difference was seen in the toxicities between the two methods of administration of UFT. Moreover, the concentration of 5-FU in the tumor tissue treated with UFT intermittently was significantly higher than that by daily administration method.     

Antitumor activity of combination treatment combining gemcitabine with topotecin against human lung cancer xenografted in nude mice

Gemcitabine is a new deoxycytidine derivative that shows a distinguishing, potent antitumor activity against various human tumor lines transplanted to nude mice. We have investigated the antitumor activity of gemcitabine combined with cisplatin (CDDP) or vindesine (VDS) using a lung cancer line, H-74, that was insensitive to almost all antitumor drugs and relatively insensitive to gemcitabine. We found that the antitumor effects of gemcitabine combined with CDDP or VDS were more potent and lasted longer than that of each drug alone, without an increase in side effects such as body weight loss. In this study, the antitumor activity of combined gemcitabine with topotecin (CPT-11) was evaluated using a similar method for 8 weeks, including a 4-week treatment period and a subsequent 4-week drug-free period, with reference to tumor growth inhibition rate, histological changes, and side effects. The treatment combining gemcitabine with CPT-11 administered at each 1/2 MTD showed an additive effect at 4 and 8 weeks after start of administration. Furthermore, no remarkable side effects were observed. Since these study results demonstrated that gemcitabine combined with CPT-11 increased and prolonged the antitumor activity without increasing side effects such as body weight loss, it is expected that CPT-11 could be one of the useful drugs used in combination with gemcitabine for lung cancer therapy.     

Effect of cholecystokinin on human cholangiocarcinoma xenografted into nude mice

Gastrointestinal polypeptide hormones regulate growth of various normal gastrointestinal tissues as well as certain visceral cancers. Since cholecystokinin (CCK) promotes growth of normal biliary tract, we sought to determine whether CCK affects the growth and metabolism of human cholangiocarcinoma line SLU 132. Twenty-six nude mice with s.c. xenografts of this cancer received either CCK octapeptide (50 micrograms/kg/dose) or 0.9% NaCl solution (saline) twice a day i.p. for 14 days. Tumor volume was calculated from Vernier caliper measurements. At sacrifice on Day 15, tumors were excised, weighed, and examined histologically. DNA, RNA, and protein were measured in the xenografted carcinomas. Because this cholangiocarcinoma produces carcinoembryonic antigen (CEA), we obtained serum at sacrifice for CEA radioimmunoassay and also tumor tissue for CEA immunolabeling with murine anti-CEA monoclonal antibody. Serum CEA levels were 90% higher in the CCK-treated group. Tumor tissue in the CCK-treated group also contained more CEA than did the controls. Mean tumor volume increased significantly in the saline group during the 14-day treatment period, whereas mean tumor volume did not increase significantly in the CCK group. Exogenous high-dose CCK thus appears to increase production and release of CEA from SLU-132; it also appears to retard growth of this tumor line in the nude mouse.     

Radiolocalization of xenografted human lung cancer with monoclonal antibody 8 in nude mice

A monoclonal antibody (MAb) 8 [immunoglobulin G3 (IgG3)], directed against a Mr 48,000 human lung cancer-associated antigen, was radiolabeled with either 125I or 131I, and its biodistribution was studied in nude mice bearing human lung cancer (TKB-2) over a 7-day period. 125I-labeled MAb 8 increased its binding to the tumor during the period, while the binding of 125I-labeled control IgG3 declined after initial uptake. At Day 7, percentages of injected dose of 125I-labeled MAb 8 bound to the tumor rose to 7.4%, which was a 4.4-fold increase from Day 1 and 16-fold binding of 125I-labeled control IgG3 at the same day. Tumor:blood ratios became 2.7:1 at Day 7, and tumor:liver, tumor:spleen, and tumor:kidney ratios were more than 9:1. Normal organs showed no significant uptake of 125I-labeled MAb 8, compared with those of 125I-labeled control IgG3. A clear image of the xenografted tumor was obtained at Day 5, and it further improved at Day 7, when 60% of whole body radioactivity was localized to the tumor. Autoradiography of the mouse with tumor confirmed the excellent localization of 125I-labeled MAb 8 to the tumor, although the radioactivity of the tumor was not uniformly distributed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that most of the radioactivity was present at the tumor in the form of degraded immunoglobulin. MAb 8 has a potential usefulness in the diagnosis and treatment of lung cancer.     

多西紫杉醇联合曲格列酮对人前列腺癌裸鼠移植瘤的抑制作用

目的:探讨多西紫杉醇联合曲格列酮(troglitazone,TGZ)对人前列腺癌裸鼠移植瘤的抑制作用,并初步探索其作用机制.方法:建立人前列腺癌裸鼠移植瘤模型,观察多西紫杉醇联合TGZ对移植瘤生长的抑制作用,FCM法检测移植瘤细胞的凋亡率,免疫组织化学法检测移植瘤组织中bcl-2和bax蛋白的表达情况.结果:与对照组比较, 多西紫杉醇联合TGZ可明显抑制人前列腺癌裸鼠移植瘤的生长,肿瘤体积和质量明显下降,细胞凋亡率明显上升;免疫组织化学法检测结果显示,移植瘤组织中bax蛋白的表达明显增强,bcl-2蛋白的表达明显减弱.结论:多西紫杉醇联合TGZ对前列腺癌有一定的抑制作用,其作用机制可能是通过上调促凋亡蛋白bax的表达及下调抗凋亡蛋白bcl-2的表达,导致肿瘤细胞加速凋亡而实现的.     

Chromosome findings in human neuroblastomas xenografted in nude mice

Chromosomes were successfully studied in 8 of 9 human neuroblastomas (NBs) xenografted in nude mice. Structural abnormalities in the short arm of chromosome #1 were found in 6 of the 8 tumors; these included nonreciprocal translocations and simple deletions. The breakpoints were distributed between 1p11 and 1p34, and all of them had lost the terminal portion of 1p (1pter----1p34). Double minutes (DMs) and homogeneously staining regions (HSRs) were observed in 7 tumors; 6 had either DMs or HSRs, and one had some cells with DMs and other cells with HSR. Only one tumor had neither DMs, nor HSRs. Our study revealed that structural abnormalities in the NB xenografts were essentially the same as those in the NB cell lines and fresh tumors reported previously, and that DMs and HSRs were seen in most NB xenografts as frequently as in NB cell lines.     

Therapeutic response to taxol of six human tumors xenografted into nude mice

Summary To test the antineoplastic activity of taxol, a natural product isolated from yew (Taxus baccata L.), six human tumors transplanted into athymic mice were used (primary tumors of breast, endometrium, ovary, brain, lung and a recurrence of tongue tumor).While the growth rates varied with the histopathological characteristics of different tumor types, all mice were treated at a mean tumor volume of 200±8 mm³.Taxol was given SC at a dose level of 12.5 mg/kg per injection per day for 5 consecutive days out of 7 over a period of 3 weeks. With this schedule antitumor responses were obtained in all of the six neoplasms xenografted into nude mice. In the case of the ductal carcinoma of the breast total tumor regressions were observed in four of the five treated animals. In the five other experimental models taxol produced significant growth delays.We believe that the results of these initial tests on the nude mouse — human tumor xenograft system are convincing and justify clinical assessment of this drug.Abbreviations used VT/VC % (mean tumor volume in treated mice ÷ mean tumor volume in control mice) x 100 - WT/WC % (mean tumor weight in treated mice ÷ mean tumor weight in control mice) x 100 The work described in this paper was supported by the CNRS as part of its Programme Interdisciplinaire de Recherche sur les Bases Scientifiques des Médicaments (PIRMED)     

Evaluation of cardiotoxicity in new anthracycline analog ME 2303. ME 2303 Study Group

ME 2303 is a new anthracycline analog which differs from adriamycin in the sugar moiety. ME 2303 displays a higher antitumor activity against L 1210 and P 388 Leukemia than adriamycin. To evaluate the cardiotoxicity of ME 2303, ECG tracings (21 patients) and Holter ECGs (9 patients) were recorded before and after the administration of ME 2303 for various malignancies (mean dose 123.8 mg/m2), and some of the electrocardiographic parameters were analyzed. Control ECGs were normal in 17 patients, in 4 patients minor ECG findings like sinus tachycardia (2 patients), low voltage (1 patient) and flattening of the T wave (1 patient) were observed. After treatment, no relevant ECG changes were observed except one case who showed a flat T in pretreatment ECG. In this patient developed ST-T changes were seen after treatment. The basic rhythm was sinus rhythm in all of the cases, and the heart rate showed no significant changes. ME 2303 had no effects on the specialized conduction system. With regard to arrhythmia, no increase in number and severity was observed. In Holter ECG no development of ST-T changes was seen after treatment.     

Chemosensitivity of human gastrointestinal and breast cancer xenografts in nude mice

Experimental chemotherapies for 15 human cancers xenografted into nude mice were performed using 14 anticancer agents including 6 drugs in clinical use. Treatment with each single agent was performed for every cancer line using the maximum tolerated dose through continuous daily (antimetabolites) or intermittent (cytocidal agents) schedules. Effectiveness of each drug was evaluated by inhibition rate (IR) calculated from mean tumor weights of both treated and untreated groups. Response to a treatment was judged as effective when the IR was higher than 58%. Response rate of each drug was as follows; MMC was 67%, UFT 67%, CPA 47%, FT-207 40%, ACNU 33%, ADR 27%, SOAz 87%, 5'-DFUR 80%, MXT 20%, Leakadine 17%, M-83 17%, CAM 0% and GANU 0%. Generally, the experimental results for each drug on the xenografts was in good accordance with the known clinical effect of each drug on the same type of cancer. On the other hand, individual cancer xenografts showed considerable differences in chemosensitivity. Some tumors were sensitive to a majority of the drugs, whereas some were resistant to many of them. Each cancer line seemed to retain individuality in its spectrum of chemosensitivity irrespective of whether it originated from the same organ or whether it was of similar histologic type. This fact suggests the necessity of selecting drugs effective to the individual tumor when considering a patients chemotherapy regime.     

Antitumor activity and metabolism of a new anthracycline-containing fluorine (ME2303) in Lewis lung carcinoma-bearing mice.

(7-O-(2,6-Dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone-14- hemipimerate (ME2303) showed a more marked growth inhibition of Lewis lung carcinoma than adriamycin (ADM). When administered to s.c. Lewis lung carcinoma-bearing mice, ME2303 in the plasma and liver was rapidly metabolized and disappeared. However, ME2303 was incorporated into the tumor at higher concentrations and remained in the tumor for a longer period than in the plasma and liver. ME2303 was metabolized to 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone (M1), the product of esterolysis, and its reduced derivative at the C-13 position (M2). Larger amounts of these metabolites were found in the analyzed tissues than in plasma. The maximum concentration of M1 in the tumor was observed at 2 h posttreatment, while the maxima in the plasma and liver were observed at 15 min. On the other hand, i.v. injection of M1 into mice showed a weaker antitumor effect than ME2303 injection, though M1 levels in the plasma and tumor were almost the same as those after administration of ME2303 at the maximum tolerated doses. Some metabolites of ME2303 were found in the tumor after administration of ME2303, but not after administration of M1. ADM remained in the analyzed tissues for a long period and ADM concentrations in the tumor were much higher than in the plasma but less than in the liver. M1 reached a concentration higher than that of ADM in the tumor, opposite to the pattern observed in the liver. The conversion process from ME2303 to M1, the metabolites and their locations in the tumor may be important for the marked antitumor effect of ME2303 in vivo.     

Malignant transformation of host cells by a human small cell lung cancer xenografted into nude mice

Malignant transformation of mouse host cells by a human small cell lung cancer (SCLC) was demonstrated by short-term in vitro cultivation of the tumor cells from a xenograft at two different transplant generations. Isoenzyme (LDH) and chromosome analysis showed that out of the 3 cell lines established from this tumor, 1 retained a human karyotype similar to that of the xenograft and 2 were murine transformed cell lines. These murine cell lines produced fibro-sarcoma-like tumors when injected into nude mice. Because of the early in vitro emergence of murine transformed cell populations, it is likely that the transformation process had occurred in vivo. Since in our experience the induction of transformation of host murine cells, also observed directly in vivo, is more frequent with SCLC than other histotypes (lung and colorectal adenocarcinoma), it is suggested that the known production of growth factor by these tumors may contribute to this transformation.     

Progression markers in metastasizing human melanoma cells xenografted to nude mice (review)

The past decade transplants of human tumors in nude mice have been increasingly used as an experimental model for local tumor growth and dissemination. A few human melanoma cell lines have been described that give rise to metastases in nude mice after subcutaneous inoculation. First we give an overview of some relevant literature with respect to the pathogenesis of tumor metastasis, models to study human cancer metastasis, neoplastic progression and the detection of antigens involved in metastasis. Finally we describe our results concerning the morphological and immunohistochemical profile of six different human melanoma cell lines and their xenograft lesions in nude mice using a set of monoclonal antibodies recognizing different categories of human melanoma-associated antigens. From the data we conclude that the nude mouse mouse model appears suitable to study the role of melanoma-associated progression markers in the pathogenesis of metastasis.     

Antitumor effect of monoclonal antibody-carboplatin conjugates in nude mice bearing human ovarian cancer cells

Background. The antitumor effect and toxicity of immunoconjugates were studied in nude mice bearing a human ovarian cancer cell line, OVA-1. Methods. We studied the tissue distribution of an anti-cytokeratin-8 monoclonal antibody (6D7) in OVA-1-bearing nude mice by giving 6D7 labelled with ¹²⁵I. The immuno conjugate consisted of 6D7 and carboplatin (6D7-conjugate), coupled via carboxymethyl dextran, and this was intraperitoneally administered to OVA-1 bearing nude mice. The tumor volume and the body weight were measured for 5 weeks. Tissue platinum concentrations in the OVA-1 tumor, blood, liver, kidney, and spleen, were measured from 3 to 120 min after administration of the conjugate. The results were compared with those in nude mice treated with nonspecific mouse IgG coupled with carboplatin (IgG-conjugate) or carboplatin alone. Results. The coupling rate of the drug to 6D7 was approximately 80%, and was stable over several measurements at various times. In-vivo accumulation of 6D7 labelled with ¹²⁵I in the OVA-1 tumors was significantly higher than that in mice that received nonspecific mouse- IgG-¹²⁵I, with tumor/ blood radioactivity ratios of 14.0 and 1.28, respectively. The tumor growth rate in mice that were administered 6D7-conjugate was (at a maximum) 40% lower than the tumor growth rate in mice administered carboplatin. The body weight of the mice that received 6D7-conjugate did not decrease during the 5-week observation period, while the body weight of the mice that received carboplatin decreased by a maximum of 10%. In addition, upon administration of 6D7-conjugate, the platinum concentration in the tumor was maintained for a longer period than after the administration of carboplatin alone. Conclusions. The tumor growth suppression effect was significantly higher in the mice bearing the OVA-1 tumor that received 6D7-conjugate than in the animals that received carboplatin alone. This difference could be caused by differences in the platinum concentrations in the tumor between the two groups. Received: November 9, 1998 / Accepted: March 23, 1999     

腺病毒介导VEGF-siRNA对荷人骨肉瘤裸鼠移植瘤生长的影响

目的:观察腺病毒介导的VEGF-siRNA对荷人骨肉瘤细胞株MG63裸鼠移植瘤生长的影响。方法:将Ad-VEGF-siRNA感染MG63,用噻唑蓝(thiazolyl blue,MTT)法检测细胞体外增殖活力,反转录-聚合酶链反应(reverse transeription-poly-merase chain reaction,RT-PCR)法检测VEGF抑制效果。建立裸鼠移植瘤模型,定期瘤内注射Ad-VEGF-siRNA,观察裸鼠致瘤率、肿瘤体积、抑瘤率及免疫组化法检测肿瘤组织中bcl-2的表达。结果:感染Ad-VEGF-siRNA能明显抑制MG63细胞的生长,瘤灶内注射Ad-VEGF-siRNA后裸鼠移植瘤的质量和体积均显著低于对照组(P<0.01)。TUNEL染色显示肿瘤细胞凋亡增加,免疫组化结果提示肿瘤组织中bcl-2表达明显减少(P<0.01)。结论:Ad-VEGF-siRNA可有效而特异地阻断VEGF基因表达,抑制裸鼠移植瘤生长,促进肿瘤细胞的凋亡。     

Antitumor activity and metabolism of BOF-A2, a new 5-fluorouracil derivative, with human cancers xenografted in nude mice

Antitumor activity of BOF-A2, a new 5-fluorouracil (5-FU) derivative, was evaluated with human gastric (H-111 and H-81), colorectal (H-143), pancreatic (H-48) and breast (H-31) cancers xenografted in nude mice. Twenty-five consecutive oral administration of BOF-A2 at 17.5 to 30 mg/kg over 4 weeks caused marked inhibition or regression (over 92% of inhibition rate) to the growth of H-81, H-143 and H-31 cancers. Moreover, BOF-A2 effected to both H-111 and H-48 which have low sensitivity to 5-FU and its known derivatives. Throughout the experiments, the mice seemed to tolerate the consecutive administration of BOF-A2 without severe toxicity. When BOF-A2 was given orally, 5-FU levels in the blood of mice was notably durative for a long time as compared to 5-FU and UFT. Furthermore, 5-FU levels in the tumor tissue tended to increase and persist much more than those in the blood. This maintenance and persistence of objective level of 5-FU in the blood would be concluded to produce a high antitumor effect of BOF-A2 against human cancers xenografted in nude mice.     

Antitumor effect of human leukocyte interferon on human osteosarcoma transplanted into nude mice

We studied the effect of human leukocyte interferon (HuIFN-α) on a human osteosarcoma (OS-OH) transplanted and passed serially in athymic mice. The growth of OS-OH was strikingly inhibited by HuIFN-α (50,000 IU/mouse), regardless of whether the interferon treatment was initiated 24 hr after tumor inoculation or 2 weeks later, when tumors had grown to an appreciable size (4–6 mm). The antitumor effect of HuIFN-α was found to be dose-dependent and a daily administration of HuIFN-α(50,000 IU/mouse) all but completely arrested the tumor growth.     

中药芪蒿合剂对裸鼠移植人体鼻咽癌的抑制作用

根据我们过去的实验，特充本实验以了解此合剂体内肿瘤作用。方法；本实验用裸鼠移植人鼻咽癌检测中药芪蒿合剂Ⅰ、Ⅱ，Ⅲ的抗肿瘤作用。结果：灌服合剂Ⅰ。在相当于１２．５ｇ生药；ｋｇ＾－１剂量下，抑制率为３５．６％，在３３．５ｇ生药；ｋｇ＾－１剂量下，抑瘤率为３６．４％和５２．５％；灌服合剂Ⅱ在２５．３ｇ生药．ｋｇ＾－１剂量下，抑瘤率为５０．５％；灌服合剂Ⅲ在２０ｇ生药ｋｇ＾－１剂量下，抑制率为３４％。