胸腺细胞移植对荷瘤鼠免疫器官的影响及其抑瘤效应

为探讨新生小鼠胸腺细胞移植对荷瘤小鼠免疫功能的影响，将新生Ｋｍ小鼠胸腺细胞移植于荷瘤Ｋｍ小鼠皮下及腹腔内，采用重量参数、组织学、组织化学及图像分析仪检测等方法进行观察。结果显示，移植组实体瘤重量轻于未移植胸腺细胞的对照组，其胸腺、脾和腋下淋巴结的重量均重于对照组。移植组淋巴结副皮质区明显增大，并可见大量管腔扩张的毛细血管后微静脉。移植组脾动脉周围淋巴鞘增厚，胸腺皮质增厚，两器官的嗜派若宁细胞增多。结果表明，新生小鼠胸腺细胞移植可增强荷瘤鼠的免疫功能，主要是细胞免疫，并能抑制荷瘤鼠肿瘤的生长     

济南假单胞菌细胞壁组分(PJ-CW)体内外抗癌作用的研究

本文报告了PJ-CW对荷瘤小鼠移植肿瘤以及肿瘤细胞株抑制作用的研究。结果显示，PJ-CW不仅对瘤细胞(EL4)和荷瘤(S180．H22)鼠肿瘤有直接抑制和抑瘤作用，且能促进LAK细胞进入瘤组织，从而保护了荷瘤鼠的免疫器官，延长其存活期。PJ-CW制剂仅含多糖与氨基酸，注射后无发热等副作用，因此是一种有发展前途的新型抗癌生物制剂。     

BCG—CW对荷瘤小鼠NK细胞杀伤活性及胸腺细胞增殖能力的影响

目的 探讨卡介苗细胞壁(BCG—CW)对荷瘤鼠脾脏NK细胞杀伤活性及胸腺细胞增殖能力的影响。方法 以小鼠脾脏NK细胞为效应细胞,以~3H—TdR标记的YAC—1细胞为靶细胞,测定NK细胞杀伤活性;胸腺细胞增殖能力采用~3H—TdR掺入法测定。结果 BCG—CW组和BCG—CW 5—Fu组荷瘤鼠脾脏NK细胞杀伤活性与肿瘤对照组比较,差异显著(P<0.05;P<0.001),而且在胸腺细胞增殖能力上也明显高于肿瘤对照组,并且与5—Fu组比较也有显著差异(P<0.001)。结论 BCG—CW对荷瘤鼠免疫系统有明显的调节作用,可增强荷瘤鼠NK细胞杀伤活性,促进小鼠胸腺细胞增殖能力。     

抗人肺单克隆体ALT-01和ALT——04的反应性及相关抗原初步鉴定

给接种人肺癌组织建立的移植瘤模型裸鼠注射同种正常小鼠(BALB/C)脾细胞,当移植瘤缩小以至消失后再给该鼠注射来自另一荷瘤小鼠的移植瘤匀浆,取该免疫裸鼠的脾细胞与骨髓瘤细胞NS-1融合,得ALT-04杂交瘤系。用人肺鳞癌细胞系LTEP-78     

肿瘤疫苗与BCG合用的抗癌疗效及其程序性细胞死亡诱导的实验研究

用肿瘤疫苗进行肿瘤免疫治疗已有八十年历史,但由于肿瘤本身抗原性较弱不足以引起有效的抗肿瘤效应,疗效不够理想,随着免疫技术发展、免疫激活剂的应用,肿瘤疫苗制剂进行主动特异免疫治疗在动物及部分人类肿瘤获得良好的效果。本试验将S180 3×10~8/ml细胞经冻融及高渗KCl进行细胞膜提取,制肿瘤(疫)疫苗,观察肿瘤疫苗与BCG(简称瘤苗)合用对荷瘤小鼠肿瘤生长、存活期及瘤细胞程序性死亡的影响,结果发现经瘤苗50μl及BCG50μl(含100μg活苗)治疗后,荷瘤小鼠肿瘤生长缓慢,存活期延长,于荷瘤(S180 5×10~6/0.2ml腋下接种)后13天,测定肿瘤大小(长径×宽径),瘤苗治疗组与荷瘤对照组分别为110±30mm与250±70mm,差异显著P<0.01,瘤苗治疗组肿瘤生长明显受抑,于荷瘤前7天应用瘤苗其抑瘤更显著,肿瘤大小为90±10mm。于荷瘤后10天记录荷瘤小鼠死亡数直至60天,两组分别为34.6±7.3天,14.6±1.3天,瘤     

集落刺激因子-1及其受体对乳腺癌荷瘤鼠肿瘤生长的影响

目的 探讨CSF-1及其受体对乳腺癌荷瘤鼠肿瘤体积以及对其免疫器官包括骨髓、胸腺、淋巴结和脾的影响。 方法 将4T1细胞（1×107/只）重悬于PBS液接种于Balb/c 小鼠左腋皮下,建立荷乳腺癌小鼠模型为实验组,同时培养相同条件的对照组。检测成瘤率,测量肿瘤体积的变化并绘制成图;成瘤后为实验组小鼠注射CSF-1及其受体,观察一段时间后同时处死两组小鼠,采用半定量RT-PCR技术检测鼠脾脏中CSF-1的表达;采用MTT比色法检测小鼠的肿瘤、脾脏、骨髓中细胞的增殖功能。 结果 4T1细胞接种后小鼠的成瘤率为100%,成瘤潜伏期平均为7~10天;实验组小鼠瘤体的增长速度快于对照组;RT-PCR的电泳结果显示,实验组小鼠的脾脏CSF-1的mRNA的表达量上升;MTT结果表明,CSF-1作用之后的实验组小鼠的肿瘤细胞和免疫细胞增殖活性升高,发挥了强大的免疫抑制功能,促进肿瘤的增长;增殖活跃的骨髓和脾细胞呈现免疫抑制表型。 结论 CSF-1及其受体对乳腺癌荷瘤鼠的肿瘤的生长有促进作用。     

CPP-Id-DC疫苗对淋巴瘤荷瘤鼠的免疫治疗作用和对淋巴瘤细胞攻击的免疫保护效应

目的了解树突状细胞(DC)疫苗对淋巴瘤荷瘤鼠的免疫治疗作用及疫苗免疫对淋巴瘤细胞攻击的免疫保护效应。方法将小鼠淋巴瘤A20细胞接种BAL B/c小鼠,建立荷瘤鼠模型,分别接种Id-DC和CPP-Id-DC疫苗,观察荷瘤鼠肿瘤大小变化及生存时间。小鼠预先分别接种Id-DC和PP-Id-DC疫苗,然后以A20细胞攻击,观察其成瘤率及生存时间。均注射PBS作为对照。结果接种PBS的荷瘤鼠肿瘤生长快,中位生存时间为33.4 d;接种Id-DC的荷瘤鼠,个别小鼠肿瘤生长减慢,中位生存时间为40.4 d,与PBS对照组相比,差异无统计学意义;而接种CPP-Id-DC的荷瘤鼠肿瘤生长明显减慢,5只小鼠中,1只肿瘤停止生长,1只肿瘤逐渐缩小、消退,90 d内的中位生存时间为70.8 d,明显长于PBS对照组和Id-DC接种组(P<0.01)。以Id-DC预防接种的小鼠予A20细胞攻击后大部分成瘤(4/5),成瘤时间为7～12 d,较PBS对照组略延长,中位生存时间为44.8 d;CPP-Id-DC接种组小鼠60 d内均无肿瘤生长。结论CPP-Id负载的DC疫苗治疗B细胞淋巴瘤优于单纯Id负载的DC疫苗,可以提高抑瘤率和延长荷瘤鼠的生存时间,可在小鼠体内产生对A20淋巴瘤细胞攻击的免疫保护。     

腺病毒介导IL-2基因转染的瘤苗体内抗肿瘤作用

目的 :探讨重组腺病毒介导的 IL- 2基因转染的瘤苗的体内抗肿瘤作用及其免疫学机制。方法 :应用腺病毒介导的鼠 IL- 2基因转染 CT2 6小鼠结肠癌细胞 ,灭活后用作瘤苗治疗荷瘤小鼠 ,观察皮下肿瘤生长及其存活期。采用乳酸脱氢酶释放法检测荷瘤小鼠脾细胞 CTL、L AK、NK细胞的杀伤活性。结果 :鼠 IL- 2基因转染瘤苗治疗能显著抑制荷瘤小鼠皮下肿瘤生长并明显延长其存活期 (P<0 .0 1)。体内免疫功能检测表明 ,鼠 IL- 2基因转染疫苗治疗组小鼠脾细胞 CTL 活性、L AK活性和 NK活性显著高于对照组 (P<0 .0 1)。结论 :腺病毒介导鼠 IL- 2基因转染的瘤苗体内具有较强的抗肿瘤效应 ,其机制可能是提高了荷瘤小鼠特异性和非特异性抗肿瘤免疫反应     

癌得清注射液的抗癌作用

本文用金黄色葡萄球菌（Staphylococcusaureus）、乙型溶血性链球菌（StreP－tococcushemolyticus）、卡介苗（BCG）、伤杆菌（Salmonellatyphi）等多种细菌抗原免疫SD大鼠，并从其脾脏、胸腺等淋巴组织通过透析的方法获得透析外液，再加上构才己等中药透析的小分子（MW≤10KD）物质，制备成混合制剂（癌得清）。然后以DBA／2小鼠荷L5178Y、P815肿瘤为模型，分别在肿瘤细胞接种后及接种前后腹腔注射上述制剂，观察其抑瘤作用和荷瘤小鼠脾细胞NK、LAK活性及产生IL－2活性的影响。结果表明，该制剂可明显抑制L5178Y、P815肿瘤生长并能显著增强荷瘤小鼠脾脏NK、LAK活性，增强脾细胞产生IL－2的能力。     

利用gp96-肽复合物免疫小鼠脾淋巴细胞治疗H22肝癌的实验研究

目的探讨肿瘤细胞中提纯的热休克蛋白gp96-肽复合物的特异性肿瘤免疫作用对小鼠脾淋巴细胞的影响及其抗瘤作用和机制。方法将经gp96-肽复合物免疫过的小鼠的脾淋巴细胞作为效应细胞,用M TT法测定其体外细胞毒性;用gp96-肽复合物免疫小鼠的脾淋巴细胞进行特异性免疫腹腔回输,观察荷瘤鼠的生存时间;将上述效应细胞注射入直径约1 cm的小鼠皮下移植肝癌内,观察其抗瘤效果;用透射电镜观察瘤细胞的变化。结果gp96-肽复合物免疫小鼠的脾淋巴细胞较未经免疫小鼠脾淋巴细胞对靶细胞的杀伤率显著提高;gp96-肽复合物免疫小鼠脾淋巴细胞治疗组的小鼠瘤重最小,与各对照组相比差异有显著性;体内回输特异性免疫脾淋巴细胞显著提高了H 22荷瘤小鼠的生存时间。结论经gp96-肽复合物免疫激活的淋巴细胞,其毒性杀伤作用可能是引起肿瘤细胞凋亡的重要原因。     

Suppression of Metastatic Murine Ovarian Cancer Cells by Transduced Embryonic Progenitor Cells

Ovarian cancer is the leading cause of death among gynecological malignancies. Chemotherapy alone is not sufficient to achieve long-term survival of the patient with advanced stage ovarian cancer. Although cancer immune therapy has long been expected as a new modality for ovarian cancer, very few trials have been clinically successful. One of the reasons for the failure in practical immune therapy is the immune-suppressive cancer microenvironment. We have reported that immune-suppressive molecules including PD-L1, Cox or ULBP-2 are expressed in human ovarian cancer, and they suppress local tumor immunity by disturbing CD8+T cell infiltration. Thus, we attempted to develop an immune therapy that can target multiple metastatic foci and increase CD8+T cell infiltration by altering local tumor environment. Endothelial progenitor cells (EPC) were transduced with the chemokine CCL19. When injected intravenously, this "immune-stimulatory EPC" was incorporated efficiently into local tumor vessels, and exerted an anti-tumor effect in a subcutaneous tumor model, a lung metastasis model and a peritoneal dissemination model. The anti-tumor effect was not observed when immunodeficient mice were used for the experiment, suggesting that the effect is mediated by immune cells. These results suggest that EPC are ideal carriers with which to deliver immune-stimulatory signals to multiple remote metastases. Alteration of local immune environment by this method may be used in the future for individualized cancer immune therapy.     

Curdione Inhibits Proliferation of MCF-7 Cells by Inducing Apoptosis

Background: Curdione, one of the major components of Curcuma zedoaria, has been reported to possessvarious biological activities. It thus might be a candidate anti-flammatory and cancer chemopreventive agent.However, the precise molecular mechanisms of action of curdione on cancer cells are still unclear. In this study,we investigated the effect of curdione on breast cancer. Materials and Methods: Xenograft nude mice were usedto detect the effect of curdione on breast cancer in vivo; we also tested the effect of curdione on breast cancer invitro by MTT, Flow cytometry, JC-I assay, and western blot. Results: Firstly, we found that curdione significantlysuppressed tumor growth in a xenograft nude mouse breast tumor model in a dose-dependent manner. In addition,curdione treatment inhibited cell proliferation and induced cell apoptosis. Moreover, after curdione treatment,increase of impaired mitochondrial membrane potential occurred in a concentration dependent manner.Furthermore, the expression of apoptosis-related proteins including cleaved caspase-3, caspase-9 and Bax wasincreased in curdione treatment groups, while the expression of the anti-apoptotic Bcl-2 was decreased. Inhibitorsof caspase-3 were used to confirm that curdione induced apoptosis. Conclusions: Overall, our observations firstsuggested that curdione inhibited the proliferation of breast cancer cells by inducing apoptosis. These resultsmight provide some molecular basis for the anti-cancer activity of curdione.     

Antitumor activity mediated by double-negative T cells

Allogeneic lymphocytes are potent mediators of leukemia and lymphoma remission. The goal of this study was to determine whether single MHC class I locus-mismatched lymphocytes could generate an antilymphoma activity in the absence of graft-versus-host-disease (GVHD) and to understand the underlying mechanisms. Immunoincompetent Scid or lethally irradiated mice were challenged i.v. with a lethal dose of A20 lymphoma cells together with an infusion of single MHC class I locus mismatched splenocytes. Mice that were challenged with A20 cells alone succumbed to lymphoma between 34 and 50 days after infusion. In contrast, >75% of mice that were coinfused with single class I MHC locus mismatched splenocytes survived indefinitely (n = 20) in the absence of GVHD. Interestingly, the number of CD3(+)CD4(-)CD8(-) double-negative (DN) T cells increased 15-fold in mice that did not develop lymphoma. Both DN T cells isolated from the spleens of lymphoma-free mice and DN T cells cloned from na?ve mice were cytotoxic to A20 lymphoma cells in vitro. When DN T cell clones were infused into na?ve mice i.v. together with A20 lymphoma cells, 86% of recipient mice were protected from lymphoma onset and did not develop GVHD (n = 22). To assess whether the systemic injection of DN T cells can also suppress local tumor development, A20 cells were infused i.m., and at the same time DN T cell clones were infused either i.v. or i.m. Results indicated that DN T cells infused systemically (i.v.) could not prevent local tumor outgrowth, but DN T cells coinfused locally (i.m.) prevented local tumor development in 91% of animals (n = 11). Furthermore, we demonstrate that primary DN T cells were also able to prevent tumor growth in 75% of mice when infused together with A20 cells i.m. (n = 12). Together, these results demonstrate that an antilymphoma activity can be generated in mice without causing GVHD. Furthermore, DN T cells can suppress lymphoma cells in vivo and in vitro, suggesting that DN T cells could be used as a novel strategy for the treatment of lymphoma.     

Overexpression of Bcl-xL in Human Breast Cancer Cells Enhances Organ-Selective Lymph Node Metastasis

Lymph node metastasis are the first prognostic factor in breast cancer diagnosis and an early event in metastatic spread. To assess the role of anti-apoptotic proteins in lymph node metastatic progression of human breast cancer cells we analyzed the metastatic activity of MDA-MB-435 cells transfected with the Bcl-xL gene, after orthotopic inoculation in Nude Balb/c and in SCID mice. The luciferase gene was introduced by permanent transfection in the 435/Bcl-xL and 435/Neo cells and used as a tumor marker to measure the number of tumor cells lodged in lymph nodes. We found that 435/Bcl-xL tumor cells had enhanced organ-specific metastatic activity, preferentially lodging in peripheral lymph nodes, where at 45 days post-implantation we found 7 x 10(6) +/- 6 x 10(6) 435/Bcl-xL.luc and 2 +/- 1.1 435/Neo.luc luciferase tagged tumor cell equivalents (TCEs). Metastases were abrogated in mice in which orthotopic tumors were induced with 435/Bcl-xL-antisense cells. Additionally, in vitro experiments show that in 435 cells Bcl-xL-antisense can override the emergence of resistance to apoptosis induced by TNF- alpha and TGF- beta in cells overexpressing Bcl-xL, increasing also adhesion to extracellular matrix proteins. These results point to the relevance of Bcl-xL overexpression inducing lymph node metastasis of breast cancer cells, and to the value of this gene as a target for therapy in order to prevent metastasis.     

Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis

Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis.     

Immunoregulation of Murine Plasmacytoma I. Generation of Anomalous Killer Cells in Vitro by Cocultivation with MOPC 104E

Murine plasmacytoma MOPC 104E-KI81 is a tissue culture cell line of MOPC 104E derived from BALB/c mice. MOPC 104E-KI81 implanted subcutaneously in syngeneic normal mice regresses spontaneously after an initial growth of about 10 mm. Mice that regressed tumors or mice immunized intraperitoneally with mitomycin C-treated MOPC 104E-KI81 myeloma could reject subsequent challenge of viable KI81 myeloma cells. In contrast to euthymic mice, T-cell-deficient athymic nude mice developed subcutaneous tumors after challenge and died from progressive tumor growth, suggesting the critical role of T cells in tumor regression. In vitro induction of cytotoxic cells was used to define the immunologic mechanism by which the host can suppress tumor growth. Spleen cells from immune mice did not show cytolytic activity in ⁵¹Cr release cytotoxicity assay, but showed inhibitory action of tumor proliferation in vitro at an effector cell to target cell ratio of 500:1 in a [³H]thymidine incorporation assay. To determine if cytotoxicity could be induced against MOPC 104E-KI81 cells, in vitro sensitizing cultures were studied. We have demonstrated that normal BALB/c spleen cells became cytotoxic against MOPC 104E-KI81 cells after 5 days cultivation with mitomycin C-treated stimulator cells at an optimal responder to stimulator cell ratio of 5:1. Treatment of anti-Thy-1.2 serum plus complement abolished cytotoxic activity of effector cells. Cytotoxic cells lysed not only MOPC 104E-KI81 cells used for stimulation but also H-2^k osteosarcoma cells. It was concluded that Thy-1.2-positive cytotoxic cells with nonspecific anomalous reactivity could be induced in murine plasmacytoma-stimulating cultures.     

Combining Molecular Targeted Drugs to Inhibit Both Cancer Cells and Activated Stromal Cells in Gastric Cancer

Recent studies have revealed that PDGF plays a role in promoting progressive tumor growth in several cancers, including gastric cancer. Cancer-associated fibroblasts, pericytes, and lymphatic endothelial cells in stroma express high levels of PDGF receptor (PDGF-R); cancer cells and vascular endothelial cells do not. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitor (nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mice model of human gastric cancer. Expression of PDGF-B and PDGF-Rβ mRNAs was associated with stromal volume. Treatment with nilotinib did not suppress tumor growth but significantly decreased stromal reactivity, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. Nilotinib and everolimus in combination reduced both the growth rate and stromal reaction. Target molecule-based inhibition of cancer-stromal cell interaction appears promising as an effective antitumor therapy.     

Ineffectiveness of Doxorubicin Treatment on Solitary Dormant Mammary Carcinoma Cells or Late-developing Metastases

Breast cancer is noted for long periods of tumor dormancy and metastases can occur many years after treatment. Adjuvant chemotherapy is used to prevent metastatic recurrence but is not always successful. As a model for studying mechanisms of dormancy, we have used two murine mammary carcinoma cell lines: D2.0R/R cells, which are poorly metastatic but form metastases in some mice after long latency times, and D2A1/R cells, which form more numerous metastases much earlier. Previously we identified a surprisingly large population of dormant but viable solitary cells, which persisted in an undivided state for up to 11 weeks after injection of D2.0R/R cells. Dormant cells were also detected for D2A1/R cells, in a background of growing metastases. Here we used this model to test the hypothesis that dormant tumor cells would not be killed by cytotoxic chemotherapy that targets actively dividing cells, and that the late development of metastases from D2.0R/R cells would not be inhibited by chemotherapy that effectively inhibited D2A1/R metastases. We injected mice with D2A1/R or D2.0R/R cells via a mesenteric vein to target liver. We developed a doxorubicin (DXR) treatment protocol that effectively reduced the metastatic tumor burden from D2A1/R cells at 3 weeks. However, this treatment did not reduce the numbers of solitary dormant cells in mice injected with either D2A1/R or D2.0R/R cells. Furthermore, DXR did not reduce the metastatic tumor burden after an 11-week latency period in mice injected with D2.0R/R cells. Thus, apparently effective chemotherapy may spare non-dividing cancer cells, and these cells may give rise to metastases at a later date. This study has important clinical implications for patients being treated with cytotoxic chemotherapy.     

Influence of irradiation of a primary tumor on the labeling index and estrogen receptor index in a distant tumor focus

The present investigation reaffirms our observation that removal of a C3H mouse mammary adenocarcinoma results in a perturbation of tumor cells in a metastatic focus. An increase occurs in the proportion of cells undergoing DNA synthesis (labeling index, LI), and a decrease occurs in the proportion demonstrating estrogen receptor (ER index; ERI). The changes are transient but of sufficient duration and magnitude to produce an increase in the size of a distant tumor. This study was conducted to determine whether cytoreduction of a primary tumor by irradiation would produce a similar change in metastatic tumor cells and whether preoperative radiation would obtund the effect of primary tumor removal. The administration of a maximum tolerated dose of radiation (50 Gy) to a primary tumor produced a significant (p less than 0.001) increase in LI and decrease in ERI of a lesser magnitude than that observed following surgical removal of the primary tumor, but still sufficient to enhance the growth of a metastatic focus. Whereas, there was almost a 50% increase in LI in a metastasis 1 and 3 days following removal of a primary tumor the increase was only 13% three days after radiation. There was a 20% decrease in ERI 3 days following radiation and a 37% decrease at that time following tumor removal. Preoperative irradiation of a primary tumor 1, 3, or 5 days prior to tumor removal, obtunds the increase in LI and decrease in ERI following operation. Radiation the day before surgery was most effective because the changes in a distant focus occurring as a result of the radiation and of the surgery were prevented. The clinical relevance of these observations deserves further consideration.     

Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy

Human plasminogen-derived angiostatin is one of the most potent antiangiogenic agents currently known. However, it is unclear whether angiostatin is also effective against accelerated tumor growth induced by local up-regulation of growth factors, including angiogenesis stimulators, such as in regenerating liver. Prior to addressing this question, we tested, in mice, whether continuous administration of angiostatin could improve its biological effects. This assumption was based on the relatively short half-life of angiostatin in mice, as well as on the theoretical necessity to suppress tumor-induced angiogenesis continually. The findings presented here clearly indicate continuous administration to be superior to the conventional twice-daily bolus injections. Using the maximally effective regimen of 100 mg/kg/day via s.c. pump infusion, we found angiostatin to not only suppress s.c. primary tumors but also to significantly inhibit the outgrowth of colorectal hepatic metastases in resting liver and even to inhibit accelerated tumor growth in regenerating liver after 70% partial hepatectomy. In conclusion, angiostatin could play an important role in patients subjected to partial hepatectomy to prevent outgrowth of residual micrometastases, provided it is administered continuously to obtain maximal biological effects.