抗瘤药与胸腺素对小鼠脾细胞自然杀伤活性的影响

本文用~3H—TdR释放法检测了平阳霉素、阿霉素及胸腺素对BALB/C小鼠脾细胞杀伤YAC—1瘤细胞活性影响。结果显示一定量的平阳霉素除了能直接杀伤瘤细胞外,也能增强脾细胞NK样杀伤活性;并证明阿霉素有相同的作用;当平阳霉素、阿霉素分别与胸腺素合用后,这种增强作用更为明显。     

局部麻醉药对抗癌药物的体内外增效作用的研究

用体外培养的Eca-109细胞观察了阿霉素(ADM)和平阳霉素(PYM)单用或与局麻药普鲁卡因和利多卡因合用时的细胞毒作用,结果表明:局麻药在本身无细胞毒性浓度下与ADM或PYM联合应用时,可显著加强ADM和PYM的细胞毒作用,且随局麻药剂量增加增效作用加强,但各联合用药组之间的增效程度没有差异。普鲁卡因和利多卡因在本身无体内抑瘤活性的剂量下与顺铂合用,能显著地增强顺铂对实体型S_(180)肉瘤的抑瘤作用,并能延长荷S_(180)腹水瘤小鼠的生存期。     

单克隆抗体导向平阳霉素对食管癌细胞的细胞毒特征

本文报道用葡聚糖为中介体制备抗胃癌单抗MGb_2与平阳霉素的结合物,经测算每克分子抗体可携带60～70克分子的药物。在结合物制备过程中抗体活性无明显丧失,结合物能与靶细胞特异结合。体外细胞毒试验证实,结合物对靶细胞(食管癌细胞ECA—109)具有较强的选择性杀伤作用,优于游离平阳霉素及无关抗体结合物;对非靶细胞则毒性明显减弱。提示该免疫结合物可能会成为一种较好的抗体导向化疗药物。     

肿瘤坏死因子和(或)平阳霉素对人食管癌细胞株(Eca-109)体内杀伤作用

作者用重组人肿瘤坏死因子α(rh-TNFα)和(或)平阳霉素(PYM)对人食管癌细胞株(Eca-109)裸鼠移植瘤的抗瘤作用进行了动态观察。结果证明,rh-TNFα局部和腹腔用药组之肿瘤体积比对照组明显缩小(P<0.05);组织学显示,瘤细胞变性,核固缩、核碎裂即凋谢(Apoptosis)明显增加,核分裂相减少;且有大片状出血坏死,癌巢周围大量中性粒细胞、淋巴细胞等浸润。提示TNFα对Eca-109移植瘤细胞具有明显抑制和杀伤活性,与PYM合用可显著增强其作用。其中,TNFα的免疫调节功能在机体抗肿瘤过程中可能亦起着重要作用。     

超氧化物歧化酶对平阳霉素抗癌作用的影响

本实验用体外培养的A_(549)肺癌细胞和裸鼠体内癌细胞接种方法分别观察了超氧化物歧化酶(SOD)活性与平阳霉素抗癌作用的关系。结果发现,外加的SOD抑制剂二乙基二硫氨基甲酸钠(DDC)明显增强了平阳霉素的抗癌作用;而外加SOD后,平阳霉素的抗癌作用受到明显抑制。实验结果提示,对应用平阳霉素类抗癌药化疗的患者,在一定时间内适当给予SOD活性抑制剂,将有利于提高化疗疗效。     

硒酸酯多糖增强荷瘤小鼠免疫功能和自身肿瘤杀伤活性的作用

本文研究了硒酸酯多糖(KSC)对荷S180肉瘤小鼠NK细胞活性、LAK细胞活性、IL-2分泌能力和自身肿瘤杀伤活性(ATK)的影响及抑癌效应.结果表明,KSC(40mg/kg·d×9d,ig)能增强荷瘤鼠NK细胞和LAK细胞活性,促进脾细胞产生IL-2,增强ATK活性;加强环磷酰胺(Cy,20mg/kg·d×9d,ip)的抑瘤作用,并能拮抗Cy对免疫活性细胞的抑制效应.体外用rIL-2激活荷瘤鼠脾淋巴细胞可诱生或增强ATK活性.本研究结果提示,KSC上调肿瘤宿主NK细胞和LAK细胞活性及IL-2的分泌水平,增强ATK活性,可作为生物反应调节剂(BRM)应用于肿瘤生物治疗.     

阿霉素对肿瘤细胞钠泵活性的影响

本文以~(86)Rb 示踪法观察阿霉素体外对艾氏腹水瘤细胞钠泵转运活性影响。结果:阿霉素体外作用12小时,四种不同浓度(0.2,0.4,0.6,1μg/ml)的抑制率分别为12%,32%,49%,68%;1μg/ml 阿霉素与瘤细胞作用不同时间(0.5,1,6,12小时)的抑制率分别为0%,25%,40%,68%。而阿霉素体外对瘤细胞杀伤和蛋白合成抑制的有效浓度分别为0.4μg/ml 和1μg/ml。提示钠泵活性改变在抗癌药阿霉素作用下,出现较早,抑制程度较重。     

Manumycin与DDP、PYM、5-FU、ADR联合的体外抗舌癌作用

目的：探讨Manumycin（手霉素）与常用舌癌化疗药物顺铂、5-氟脲嘧啶、平阳霉素、阿霉素联合作用于舌鳞癌Tca8113的细胞毒作用。方法：细胞毒测定以Mrrr法；单药细胞毒测定以半倍浓度梯度设计；联合用药细胞毒测定以Chou TC中效原理设计。结果：Manumycin以及顺铂、5-氟脲嘧啶、平阳霉素、阿霉素单独应用对Tca8113均有明显的细胞毒作用。联合用药显示在相应比例剂量条件下。Manumycin与顺铂联合（3.75：1）后呈拮抗作用，Manumycin与5-氟脲嘧啶联合（0.75：1）作用后，低浓度联合相互拮抗，而高浓度联合时明显协同，Manumycin与平阳霉素（0.75：1）、阿霉素联合（30：1）作用后呈相互协同的作用（CI〈I）。结论：Manumycin与平阳霉素、阿霉素以及与5-氟脲嘧啶高浓度联合作用于Tca8113细胞呈相互协同的细胞毒作用。     

树突状细胞对肿瘤浸润淋巴细胞抗小鼠肝癌活性影响的研究

目的探讨H22细胞全细胞性抗原致敏的DC激活的TIL体外抗小鼠肝癌活性,并将H22-DC-TIL过继免疫荷瘤小鼠,研究其对荷瘤小鼠免疫功能的影响及抑瘤作用。方法从小鼠四肢长骨骨髓中获取DC,应用粒/巨噬细胞集落刺激因子(GM-CSF)、白介素-4(IL-4)和肿瘤全细胞性抗原致敏DC,然后用DC激活TIL,观察TIL在体外对H22细胞、Hepal-6细胞和B16细胞的杀伤活性;检测应用H22-DC-TIL后荷瘤小鼠的脾淋巴细胞的NK、LAK、CTL活性、血清TNF活性、抑瘤作用以及瘤体病理改变,并与对照组相比较。结果①H22-DC-TIL具有很强的对H22细胞杀伤活性[杀伤率为(71.31±3.11)%],明显高于其对Hepal-6和B16细胞的杀伤活性[杀伤率分别为(50.11±3.03)%,(30.31±2.89)%],也明显高于未经DC激活的TIL、H22-DC-脾淋巴细胞和未经DC激活的脾淋巴细胞对H22细胞杀伤活性[杀伤率分别为(49.80±3.21)%,(48.76±3.60)%和(19.23±2.71)%]和对Hepal-6细胞杀伤活性[杀伤率分别为(39.40±3.21)%,(38.62±2.87)%和(18.73±2.40)%]以及对B16细胞杀伤活性[杀伤率分别为(26.38±2.51)%,(25.82±2.70)%和(18.34±3.01)%],同时B16-DC-TIL(TIL来源于H22瘤体)也可诱导相对较低的对B16细胞的特异性细胞杀伤活性。②H22-DC-TIL可明显诱导提高荷瘤脾淋巴细胞NK、LAK和CTL活性[活性为(30.43±1.35)%、(31.40±1.80)%、(35.30±1.20)%],并可检测到血清TNF水平明显上升[血清TNF为(40.41±1.85)U/ml],它们均达正常对照组水平,与未经DC激活的TIL组、H22-DC-脾淋巴细胞组、未经DC激活的脾淋巴细胞组、生理盐水组分别对应比较,差异均有显著性(P<0.01)。该组瘤体内淋巴细胞浸润程度也高于对照组,其瘤体生长明显受到抑制。结论①H22-DC-TIL可产生很强的体外针对H22细胞的特异性杀伤活性。②H22-DC-TIL具有很强的特异性抗小鼠肝癌作用。     

枸杞多糖增强人树突状细胞抗肿瘤的机制

 目的 观察枸杞多糖对树突状细胞抗肿瘤的增强作用。 方法 分离人外周血单核细胞,体外培养其成为未成熟树突状细胞和成熟树突状细胞。用冻融法制备肝癌细胞的全抗原并致敏未成 熟树突状细胞;通过混合淋巴细胞实验,获取成熟树突状细胞激活的特异性效应T细胞。用MTT法测定效应T细胞对肝癌细胞的杀伤率。观察枸杞多糖在树突状细胞的成熟及T细胞的激活、增殖和杀瘤过程中的作用。 结果 枸杞多糖能促进树突状细胞的成熟, 转染了人肝癌细胞的全抗原的mDC可特异地激活T细胞为效应T细胞。效应T细胞可特异性地 杀伤人肝癌细胞,而对不相关的MG 63细胞无特异性的杀伤作用。 单独对T细胞无明显的增殖能力,但并且能增强效应T细胞的增殖能力和杀瘤活性。 结论 枸杞多糖能促进树突状细胞成熟和增强效应T细胞的增殖和杀伤肿瘤的活性。     

Immunomodulation by adriamycin - effect on the production of cytotoxic and inflammatory antitumor immune-responses

We have recently demonstrated in a mouse renal adenocarcinoma tumor system that the antitumor effect of adriamycin (ADM) in combination with interleukin-2 (IL2) is superior to treatment with either ADM or IL2 alone. Based on this observation we postulated that modulation of host's immune competence by ADM and/or IL2 may be partly responsible for the antitumor effects of the combination treatment. Indeed, pretreatment with ADM was found to potentiate the production of both cytotoxic and non-cytotoxic immune responses. A single dose of ADM significantly increased the number of nucleated cells in the spleen in a time related fashion. A small but selective increase in CD4+ cells without an apparent change in CD8+ subset of T cells was observed following treatment with ADM. ADM potentiated augmentation of NK activity by IL2, but had no effect on the production of lymphokine activated killer (LAK) cells by IL2. In contrast, treatment with a combination of ADM and IL2 resulted in increased LAK activity and the frequency of LAK-precursors in the spleen. ADM also enhanced the development of tumor specific inflammatory delayed hypersensitivity (DH) response. Mice expressing tumor specific DH were resistant to rechallenge with viable tumor cells and their spleen cells inhibited the tumor growth in a local adoptive transfer assay. Thus, antitumor effects of combined ADM/IL2 treatment may in part involve augmented production of cytotoxic and T cell-mediated inflammatory antitumor immune responses.     

Alterations in murine host defense functions by adriamycin or liposome-encapsulated adriamycin

Peritoneal exudate cells (PEC) from C57BL/6 mice were collected on different days following an i.p. injection of Adriamycin (10 mg/kg) as free drug (ADM) or encapsulated in multilamellar liposomes (ADM/Lip). Macrophages harvested from mice at various times (Days 4-14) after either drug treatment were responsive to in vitro lipopolysaccharide induction of tumoricidal activity, maximum response being seen on Day 7. In addition, 18 days after treatment, significant macrophage tumoricidal activity was observed only in the ADM/Lip-treated group. When supernatants from cultures of PEC obtained 7 days after treatment were assayed for interleukin 1 following lipopolysaccharide stimulation, activity was found with both ADM- and ADM/Lip-treated cells. Without lipopolysaccharide stimulation, only PEC from ADM-treated mice elaborated factor(s) with interleukin 1-like activity. Both ADM and ADM/Lip induced significant PEC-natural killer (PEC-NK) activity by Day 4, while the ADM/Lip treatment sustained PEC-NK activity more effectively than free drug at later time points (7 or 11 days posttreatment). Drug-induced PEC-NK activity (Day 7) was (a) ablated by treatment in vitro with anti-asialo GM1 antibody and complement, and (b) associated with a population of PEC nonadherent to plastic. A transient suppression of splenic NK activity was seen 4 days following either ADM or ADM/Lip administration with recovery to control level by Day 7. These data demonstrate that following ADM or ADM/Lip administration some of the changes necessary for macrophage tumoricidal activation must have occurred in vivo. Liposome encapsulation of ADM extended the duration of ADM-induced augmentation of certain host defenses.     

Lymphokine-activated killer cells in rats: analysis of tissue and strain distribution, ontogeny, and target specificity

The coculture of lymphoid cells from Fischer 344 rats with recombinant human interleukin 2 (rIL-2) resulted in the generation of lymphokine-activated killer (LAK) cells. Maximal LAK activity was obtained between 200 and 1000 units/ml rIL-2. Lymphoid cells from spleen, thymus, bone marrow, peripheral blood, and lymph nodes were able to generate LAK activity although the kinetics and magnitudes of the responses were appreciably different among these tissues. Thus, while spleen and blood lymphocytes responded quickly (by day 3) and gave the highest level of LAK activity in response to rIL-2, bone marrow and thymus cells responded only by 7 to 9 days in culture. LAK activity could be generated from a variety of rat strains regardless of whether there were high or low levels of endogenous splenic natural killer (NK) activity, but the early (day 3) response was lower in the strains with low levels of NK activity. Cells with LAK activity could lyse a variety of tumor targets including fresh ascites or fresh syngeneic solid tumor explants but could not lyse fresh normal cells including syngeneic fibroblasts, peripheral blood lymphocytes, bone marrow cells, thymocytes, or T,B blasts. The generation of LAK activity required a concomitant proliferative response and could be completely abrogated by mitomycin C, actinomycin D, or X-irradiation above 500 rads. These treatments, however, did not affect natural killer activity or short-term (4 h) IL-2-boosted NK activity. LAK activity could be generated from spleen cells obtained from rats as early as 10 days of age but could not be generated from unfractionated neonatal spleen, neonatal liver, or peritoneal macrophages. The ontogeny of the development of splenic LAK activity correlated closely to the development of concurrent natural killer activity. When mixed with an NK-resistant mammary adenocarcinoma (MADB106) and adoptively transferred to normal syngeneic recipients in standard Winn-type assays, LAK cells were effective at inducing complete tumor inhibition.     

Cellular basis for adriamycin-induced augmentation of cell-mediated cytotoxicity in culture

The cellular basis for the augmented cell-mediated cytotoxic (CMC) response seen when spleen cells from Adriamycin (ADM)-treated mice were stimulated in culture was investigated. Under conditions where mature macrophages were reduced (adherent or silica-sensitive cells removed) at time of alloantigen challenge, the cells from ADM-treated mice developed levels of CMC activity much higher than the low levels which were developed by similar subsets of cells from nontreated control mice. This indicates that ADM treatment enriched a subset of cells in spleen which was nonadherent, silica-insensitive, and nonphagocytic but was capable of providing accessory function. When mature macrophages were not removed, the capability to develop an augmented level of CMC was shown to be associated with a subset of cells from ADM-treated mice which was adherent to either plastic or nylon wool. In recombination experiments, it was found that the removal of Thy 1.2+ cells from the adherent subset from ADM-treated mice had little effect on the response, while their removal from the adherent subset from nontreated mice resulted in elevated levels of response. A similar effect was obtained when Lyt 2.2+ cells were eliminated but not when Lyt 1.2+ cells were removed. This indicates that a Thy 1.2+, Lyt 1-2+ cell, involved in regulation of the response, was missing from or failed to function in the ADM-treated population. Based on these findings, ADM apparently induces modifications in two cell subsets: (a) immature cells of the monocyte/macrophage lineage which can provide accessory function; and (b) adherent, Lyt 2+ T-cells which cooperate in maintaining levels of CMC activity at "normal" levels.     

Modification of host antitumor defense mechanisms in mice by progressively growing tumor

The EL4 lymphoma in C57BL/6 mice was used as a model to examine the effect of progressive tumor growth on a variety of cell mediated cytolytic effector functions which have been shown in other systems to have antitumor potential. The functions examined were those of cytolytic T-lymphocyte, lymphokine activated killer cells, natural killer cells, and tumoricidal macrophage (MO). The kinetics of each function displayed a unique pattern as a consequence of tumor growth, but all were inhibited in animals bearing large tumors (late tumor bearers). In cell mixing experiments it was shown that spleen cells from individual late tumor bearers were suppressive for cytotoxic T-lymphocytes, lymphokine activated killer cells, and splenic MO but not peritoneal MO or splenic natural killer cells. The suppression was nonspecific and was mediated primarily by nonadherent cells and/or their soluble products. Suppression appeared to be mediated, in part, by tumor cells in the spleen since the degree of suppressor activity associated with a particular spleen cell preparation correlated with the number of tumor cells present. Furthermore, the direct addition of viable ascites EL4 cells to response cultures or assays had similar suppressive effects as late TBM spleen cells, i.e., inhibited cytotoxic T-lymphocytes, lymphokine activated killer cells, and splenic MO but had no effect on natural killer cells or peritoneal MO. The mechanism of suppression by ascites EL4 was not determined but it was mediated by viable cells only and not due to contaminating viruses or other microorganisms.     

Interaction of recombinant interferons with recombinant interleukin-2: differential effects on natural killer cell activity and interleukin-2-activated killer cells

The ability of recombinant interferons (IFNs) to modulate recombinant interleukin-2 (rIL-2) augmentation of natural killer (NK)-cell activity and to modulate the generation of activated killer (AK) cells was examined. Incubation of murine spleen cells for 18 hr with either human rIL-2 or a human hybrid recombinant IFN alpha, rHuIFN-alpha A/D, which is active on murine cells, resulted in a dose-dependent increase in NK activity; however, recombinant murine IFN gamma, rMuIFN-gamma, had little activity. A more than additive augmentation of cytotoxicity was obtained when spleen cells were incubated with the combination of rIL-2 and rHuIFN-alpha A/D. Incubation of murine spleen cells with rIL-2 for 3 days resulted in a dose-dependent induction of AK cells which were cytotoxic to an NK-resistant tumor target cell. In contrast to the results observed on NK activity, incubation of spleen cells with rHuIFN-alpha A/D and rIL-2 inhibited AK-cell activity. Partially purified murine IFN-alpha had inhibitory activity comparable to that of rHuIFN-alpha A/D. The addition of rHuIFN-alpha A/D at the initiation of culture of spleen cells with rIL-2 (day 0) resulted in maximal inhibition of cytotoxicity; inhibition was reduced or absent if rHuIFN-alpha A/D was added on day 1 or 2 of culture. The proliferation of spleen cells incubated with rIL-2 was also inhibited by rHuIFN-alpha A/D. Addition of rMuIFN-gamma to spleen-cells and rIL-2 increased the cytolytic activity of AK cells and did not inhibit rIL-2-induced proliferation of spleen cells. Similar data were also obtained with human peripheral blood lymphocytes and recombinant cytokines. Incubation of human peripheral blood lymphocytes with rIL-2 and recombinant human IFN-alpha A (rHuIFN-alpha A) or recombinant human IFN-gamma (rHuIFN-gamma) resulted in a more than additive increase in NK activity. Human AK-cell cytotoxicity was inhibited by rHuIFN-alpha A but enhanced by rHuIFN-gamma. Thus recombinant IFNs have differential effects on rIL-2-induced cytotoxic cells, resulting in augmentation or inhibition of activity, which is dependent on both the type of IFN and the cytotoxic activity examined. These results may have important implications for the potential therapeutic use of combinations of these cytokines.     

Induction of murine lymphokine-activated killer-like cells by Corynebacterium parvum (C. parvum) in vitro: lysis of tumor cells and macrophages by C. parvum-induced killer cells.

In vitro culture of murine spleen cells with Corynebacterium parvum (C. parvum) was found to induce lymphokine-activated killer (LAK)-like cells capable of killing both natural killer (NK)-sensitive and NK-resistant tumor cells as well as syngeneic macrophages (M phi). The induction of LAK-like activity by C. parvum was significantly inhibited by anti-interleukin-2 (IL-2) or anti-interferon (IFN) alpha, beta antibody (Ab), and it was further inhibited by the combination of two Abs, suggesting that the generation of killer cells by C. parvum was dependent on IL-2 and IFN(s) produced in the culture. It was considered that M phi were important in the induction of LAK-like cells by C. parvum because the depletion of M phi from spleen cells before culture with C. parvum significantly reduced the induction of killer activity. The majority of effectors mediating both tumor cells and M phi were Thyl+ and asialo-GM1 (aGM1)+, and the lysis of M phi by C. parvum-induced killer cells could be inhibited by the addition of cold YAC-1 tumor cells and P815 tumor cells, suggesting that the same population of effectors recognized tumor cells and M phi. These results demonstrated a possibility that the killing of M phi by C. parvum-induced killer cells might down-regulate anti-tumor effects of C. parvum.     

Defective autologous mixed lymphocyte reaction (AMLR) and killer activity generated in the AMLR in cancer patients.

The autologous mixed lymphocyte reaction (AMLR) and the killer activity generated in the AMLR (AMLR-killer) in the spleen and the peripheral blood of patients with gastric cancer were investigated. The AMLR in cancer patients was suppressed, especially in the spleen, compared to that seen in controls. There was no correlation between AMLR activity and the stage status of the cancer. The cytotoxic activity of AMLR-killer cells against various tumor-cell lines was also suppressed in the spleen, and had a tendency to be suppressed in the peripheral blood of cancer patients. The autologous tumor-killing activity of AMLR-killer cells was developed in cancer patients with high AMLR activity, but was not induced in patients with low AMLR activity. Autotumor killing activity was decreased by the elimination of CD4+ cells, whereas the elimination of CD16+ cells resulted in a marked reduction in cytotoxicity against K562, indicating that the non-specific killer cells which lysed K562 were different from the specific killer cells that lysed autotumor cells. This suggests that AMLR activity is related to the differentiation and proliferation of lymphocytes with specific or non-specific cytotoxic activity and that this activity plays an important role in immune surveillance against tumors.     

硼替佐米提高耐药K562/ADM细胞对NK细胞杀伤的敏感性及其机制

目的:探讨硼替佐米提高耐药K562/ADM细胞对NK细胞杀伤敏感性的可能机制.方法:流式细胞术和real-time PCR检测硼替佐米处理前后K562/ADM细胞表面MHC Ⅰ类链相关分子A(major histocompatibility complex class Ⅰ chainrelated molecule A,MICA)蛋白和mRNA的表达,LDH释放法检测硼替佐米处理前后K562/ADM细胞对NK细胞的杀伤敏感性.结果:硼替佐米处理后,K562/ADM细胞表面MICA蛋白表达率上升[(17.03 ±4.94)％vs(23.77±5.26)％,P＜0.05];处理后K562/ADM细胞MICA mRNA的表达水平是处理前的(2.03±0.33)倍.效靶比为10∶1、20∶1时,NK细胞对硼替佐米处理后的K562/ADM细胞的杀伤率上升[(23.22±3.03)％、(30.30±0.74)％ vs(33.69±1.28)％、(41.40 ±1.97)％,P＜0.05].结论:硼替佐米提高耐药K562/ADM细胞对NK细胞杀伤的敏感性,其机制可能与硼替佐米上调K562/ADM细胞MICA表达有关.     

A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells.

Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS-209 is a novel quinoline compound, which reverses P-glycoprotein (P-gp)-mediated MDR. We previously reported that MS-209 reversed in vitro MDR of human SCLC (SBC-3 / ADM and H69 / VP) cells expressing P-gp. In the present study, we determined the therapeutic effect of MS-209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC-3 / ADM cells expressing P-gp were highly resistant to etoposide (VP-16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC-3 cells lacking P-gp expression. MS-209 restored chemosensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro. Intravenous injection with SBC-3 or SBC-3 / ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3 / ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3 / ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3 / ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3 / ADM cells to multiple organs. These findings suggest that MS-209 reversed the MDR of SBC-3 / ADM cells, but not SBC-3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS-209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.