Tumor Adjuvant Therapy Research Articles

Tumor Necrosis Factor-alpha Promotes Tumor Growth by Inducing Vascular Endothelial Growth Factor

Tumor necrosis factor (TNF)-α has been proved as an adjuvant therapy for tumor by FDA. However, the effect of chronic TNF-α expression for tumor is still controversial. In this study, we investigated the effect of low-dose TNF-α on tumor growth. We confirmed that low-dose TNF-α promoted angiogenesis of tumor in vivo, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α, the transcription factor of VEGF, were both upregulated. Our results suggested that low-dose TNF-α was a powerful activator of angiogenesis in tumor and HIF-1α-VEGF pathway seemed to be the most important molecular mechanism.

Treatment of Enneking Stage 3 Aggressive Vertebral Hemangiomas With Intralesional Spondylectomy

A retrospective review of consecutive series of Enneking stage 3 vertebral hemangiomas surgically treated at a major tertiary spine tumor center. To determine the short-term recurrence rates, pain improvement, and operative morbidity of intralesional spondylectomy combined with preoperative embolization for Enneking stage 3 vertebral hemangiomas. Aggressive vertebral hemangiomas (Enneking stage 3) often involve both the anterior and posterior columns with spinal canal and local soft tissue extension and may present with dramatic bony destruction, spinal instability, and pain accompanied with neurologic compromise. Although the current treatment paradigm for most vertebral hemangiomas is conservative management directed toward symptomatic relief, the subset of patients presenting with this rare variant requires more extensive surgical treatment. A retrospective clinical review of patients diagnosed with Enneking stage 3 vertebral hemangiomas was conducted at the University of California at San Francisco. We identified 10 consecutive cases of Enneking stage 3 hemangiomas. Average follow-up was 2.42 years. The most common presentation was pain with or without myelopathy. Three of the 10 cases were recurrences after prior partial resection and reconstruction or cement augmentation. All patients underwent preoperative embolization. Average blood loss despite embolization was 2.1 L (range: 0.8 to 5 L). Average preoperative back pain visual analog scale was 7.2 and postoperative visual analog scale was 3.1 at 6 months. On postoperative imaging, all patients had gross total resection. Six patients had staged posterior/anterior transcavitary approach and 4 patients underwent single stage posterior transpedicular spondylectomy. To date, no patient has required adjuvant radiation therapy for tumor recurrence. Our results suggest that complete wide resection of aggressive Enneking stage 3 lesions can be safely accomplished with acceptable morbidity and blood loss and significant improvement in pain and neurological status. Partial resection of stage 3 lesions, even with stabilization or vertebroplasty, may lead to early recurrence.

Imatinib as adjuvant therapy for gastrointestinal stromal tumors: a systematic review

The high risk of recurrence in resected gastrointestinal stromal tumor (GIST) highlights the need for effective adjuvant treatment. This review evaluates the clinical efficacy and safety of imatinib for adjuvant treatment of localized KIT (CD117)-positive resected GIST. Relevant studies were identified by searching several electronic databases from inception to August 2009. Searches were supplemented by examining bibliographies of included studies, searching conference proceedings and consulting experts. All study types were included. Methodological quality was assessed using published criteria. Sixteen studies met the eligibility criteria, comprising one randomized controlled trial (RCT), three phase II studies, three cohort studies and nine case reports. In the RCT, the estimated 1-year recurrence-free survival was 98% [95% confidence interval (CI), 96-100] in the imatinib group versus 83% (95% CI, 78-88) in the placebo group, corresponding to a 65% reduction in the risk of disease recurrence (hazard ratio, 0.35; 95% CI, 0.22-0.53; p < 0.0001) with an absolute recurrence-free survival difference of 15% at 1 year. Other nonrandomized studies reported similar outcomes demonstrating that imatinib used in the adjuvant setting improved recurrence-free survival. The optimum duration of adjuvant treatment, safety and efficacy is currently under investigation with two ongoing RCTs (EORTC 62024 and SSG XV111) and two nonrandomized studies (NCT00867113 and NCT00171977). This study adds to the evidence (based on one RCT and a number of observational studies) that GIST patients treated with adjuvant imatinib therapy show an improvement in recurrence-free survival compared to placebo or no treatment after resection of KIT-positive localized GIST with tolerable toxicity.

EFFICACY OF THE ENNEKING STAGING SYSTEM IN RELATION TO TREATING BENIGN BONE TUMORS AND TUMOR-LIKE BONE LESIONS

Objective: To evaluate the efficacy of the Enneking staging system for determining the prognosis, planning surgical treatment and indicating adjuvant therapy for benign bone tumors (BBT) and tumor-like bone lesions (TBL). Methods: A retrospective multicenter, descriptive, nonrandomized study was carried out on a representative sample comprising a large series of 165 patients with a total of 168 benign bone tumors and tumor-like bone lesions. The patient sample was typical, and matched the literature in all respects. All the patients were classified according to the Enneking staging system, and the initial staging of each lesion was correlated with its behavior after either conservative or surgical treatment, in order to determine the efficacy of the system. The treatment options and complications were described and analyzed. Results: The results from the treatment provided 95.2% agreement with the Enneking staging system, with a 95% confidence interval of between 90.8 and 97.9%. Of the 168 tumors treated, only eight (4.8%) could not be controlled in relation to the initial treatment indicated by the Enneking staging system. Tumors classified as active were the most prevalent, comprising 73.2% of the lesions. Tumor recurrence was significantly more frequent (p < 0.001) in the aggressive stage. All the patients staged as latent evolved to cure. The study suggested that surgery with wide margins, for aggressive lesions, could provide better lesion control, with a lower recurrence rate (p > 0.001). For latent and active lesions, the study demonstrated the efficacy of both expectant treatment and excision, with or without autogenous bone graft. Conclusion: The results confirm that the Enneking staging system was very efficient in determining the prognosis, enabling surgical planning and indicating adjuvant therapy for treatment of BBT and TBL.

Adjuvant therapy for giant cell tumor

Adjuvant therapy for giant cell tumor

Radiotherapy for pediatric brain tumors: when and how

Radiotherapy plays a central role in the treatment of pediatric brain tumors. Historically, surgical resection alone was the mainstay of treatment for pediatric CNS malignancies. During the past 75 years, radiotherapy has been incorporated into the upfront treatment of many pediatric brain tumors either as adjuvant therapy for resected tumors, definitive treatment for unresectable malignancies or as prophylactic therapy for occult microscopic disease. Many CNS malignancies, which were once universally fatal are now curable with multimodality approaches that integrate surgery, chemotherapy and radiotherapy. Unfortunately, the long-term CNS side effects of radiotherapy remain a major obstacle for survivors of childhood tumors. In this article we will discuss these issues in detail and summarize the ongoing efforts to reduce the risks of these toxicities.

Surgical treatment for choroid plexus tumors in the fourth ventricle: brain stem infiltration hinders total extirpation

The significance of surgery for choroid plexus tumors is well established, but surgical resection of those in the fourth ventricle has not been evaluated. This study reviewed five consecutive patients with choroid plexus tumors in the fourth ventricle treated in our institute between 1996 and 2005, focusing on the factors that hindered total extirpation. Two cases were choroid plexus papillomas, and three cases were choroid plexus carcinomas. Preoperative T2-weighted magnetic resonance imaging showed a diffuse high-intensity lesion in the brain stem in four patients. Infiltration into the fourth ventricle floor was apparent in all five patients during surgery, which hindered total resection of the tumors without neurological deterioration. Intraoperative bleeding was well controlled in all five patients by cauterizing the feeding arteries at the early stage of surgery through the telovelar approach. Performance status was improved in all patients postoperatively. All patients with choroid plexus carcinomas underwent radiation therapy after the surgical removal. No patient suffered tumor progression within the follow-up of 24-129 months (mean 64 months). Total resection of choroid plexus tumors in the fourth ventricle is difficult because of invasion into the fourth ventricle floor. Adjuvant therapy for choroid plexus tumors with brain stem infiltration must be established.

Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: A case–control study

Background: Giant cell tumor (GCT) of bone is a benign but locally aggressive tumor that is characterized by the presence of mononuclear stromal cells and multinucleated giant cells. Although topical adjuvants have been used in the past, local recurrence following intralesional excision of GCT of bone continues to remain a problem. The use of bisphosphonates as an anti-osteoclastic agent in the management of osteolytic bone metastases is well accepted. Furthermore in vitro studies have shown that bisphosphonates also induce apoptosis in GCT stromal cells. Therefore our clinical study aims to investigate whether the administration of bisphosphonate as an adjuvant can further decrease local recurrence following the surgical treatment of GCT of bone. Method: A retrospective case–control study was performed between 1988 and 2004. Forty-four patients with histological diagnosed appendicular GCT were included. Intralesional curettage or wide excision of the lesions was followed with cementation or biological reconstruction. Additional intravenous and oral bisphosphonates were given peri-operatively to 24 patients who were treated between 1998 and 2004. The average follow-up of the control group was 115 months while that of the treatment group was 48 months. Results: In the bisphosphonate treated group, 1 of 24 patients (4.2%) developed local recurrence. In the control group, 6 of 20 patients (30%) developed local recurrence. The difference in the recurrence rate was statistically significant between the bisphosphonate treatment group and the control group (Log Rank test p = 0.056). The effect of reduction of local recurrence was significant in patients with stage III diseases. Patients treated with bisphosphonate did not report any untoward effects. Conclusion: Clinical use of bisphosphonates as an adjuvant therapy for giant cell tumor of bone demonstrated a lower local recurrence rate. The clinical response seems to be more promising in stage III diseases.

Subclinical photodynamic therapy treatment modifies the brain microenvironment and promotes glioma growth

Photodynamic therapy (PDT) has been clinically investigated as an adjuvant local therapy for brain tumors. Therapeutic interventions intended to promote tumor cell death can also promote changes in the tumor microenvironment that could favor tumor growth. We have previously shown that PDT can activate pro-angiogenic factors in the normal rodent brain. This study seeks to further elucidate the effects of subtherapeutic doses of Photofrin-PDT on normal brain and to establish a mouse model for studying glioma progression in an environment modified by oxidative stress. Photofrin was administered to nude mice, and a defined intracranial area was illuminated with laser to deliver an optical dose equivalent to 80 J/cm(2). Three and 7 days after PDT, mice were sacrificed and brains were fixed and analyzed by immunohistochemistry. PDT treatment resulted in transient increase in cell proliferation, associated with a robust activation of astrocytes and microglia in the treated region, without causing substantial cell death. To test how this modified environment would affect glioma growth, human glioblastoma U87 cells were implanted in the PDT-treated hemisphere or in the control brain subjected to sham surgery. Significantly larger tumors were observed after 3 weeks in the PDT treated brains relative to control treatment. Our results indicate that subclinical Photofrin-PDT locally alters the brain homeostasis without inflicting significant disruption to the tissue architecture, providing a model to study the effects of the microenvironment on glioma growth, with implications for the optimization of the clinical use of PDT for brain tumors.

Evaluation of Residual Tissues after Adjuvant Therapy in Germ Cell Tumors

Objective: Germ cell tumors are the tumors sensitive for adjuvant therapy such as radiotherapy and chemotherapy. We evaluated the pathological findings of these heterogeneous tumors to determine the persistence of residual viable tumor cells after adjuvant therapy. Patients and Methods: Between 1988 and 2005, we treated 31 patients with germinoma or germinoma with syncytiotrophoblastic giant cells (STGC) and 15 patients with non-germinomatous malignant germ cell tumors (NGMGCTs). All 46 patients received a combination of chemo- and radiotherapy. A second-look operation was performed in 3 of 31 patients with germinomas or germinomas with STGC and 12 of 15 patients with NGMGCTs. The follow-up period was 2–139 months (median 95) in patients with germinomas or germinomas with STGC (group 1) and 10–202 months (median 65) in NGMGCT patients (group 2). Results: Post-treatment, 3 group 1 and 12 group 2 patients manifested residual tumors. The pathological diagnosis in group 1 patients was mature teratoma, pineal cyst, and fibrous tissue with calcification; in group 2 it was yolk sac tumor (n = 1), immature teratoma (n = 3), mature teratoma (n = 4), and necrosis or fibrous tissue (n = 4). While no group 1 patients manifested tumor cells, MIB-1-positive viable tumor cells were present in resected tissues from one-third of the group 2 patients (3 immature teratomas and 1 yolk sac tumor). Conclusion: The absence of viable tumor cells in residual tissue indicates that the combination of cisplatin-based chemo- and radiotherapy was effective in our germinoma patients. On the other hand, in patients with NGMGCTs, these cells persisted despite this combination therapy.

Expression of Eukaryotic Initiation Factor 4E in Astrocytic Tumors

Upregulation of expression of the eukaryotic initiation factor 4E (eIF4E) has been identified in breast carcinomas, squamous cell carcinomas in the head and neck regions, and transitional cell carcinomas of urinary bladder. In this immunohistochemical study, eIF4E protein expression was investigated in human brain tissue from patients without central nervous system diseases and brain biopsy tissues from patients with anaplastic astrocytoma and glioblastoma multiforme. Expression of eIF4E protein was observed in normal pyramidal neurons but not in neuroglial components. In anaplastic astrocytoma and glioblastoma multiforme, there was diffuse uniform expression of eIF4E immunoreactivity in malignant astrocytes. A similar pattern of immunoreactivity was also present in proliferative endothelial cells and vascular lining endothelial cells in glioblastoma multiforme. This study provides evidence that eIF4E is upregulated in high-grade astrocytic tumors. As in other malignancies, a high level of eIF4E may play an important role in the neoplastic transformation, angiogenesis, and tumor growth in astrocytic tumors. Because eIF4E is crucial in regulation of tumor growth, eIF4E could be a potential target for inhibitors as an adjuvant therapy for brain tumors.

Candidate genes upregulated in density dependent growth inhibition of lung cancer cells

Prognosis of lung cancer remains poor despite the recent development of new chemotherapeutic agents. Novel therapeutic strategies therefore need to be developed. The search for endogenous factors inhibiting tumor growth in a paracrine/autocrine fashion might result in a well tolerated adjuvant tumor therapy. In this study we intended to identify candidate genes for such inhibitors of tumor cell growth. Native and heat inactivated supernatants of confluent, slow growing H460 tumor cell cultures and of sparse (non confluent), fast growing H460 tumor cell cultures were tested in proliferation assays. We observed that native supernatant of confluent H460 cells contains proteins inhibiting tumor cell growth of NSCLC cell lines. Microarray gene expression analysis of sparse and confluent H460 cells exhibited overexpression of seven candidate genes in confluent, slow growing cells. The products of these genes possess cell growth inhibitory function and also exist in the extracellular compartment. The increased expression level of these genes was verified using real-time RT-PCR analysis. Further investigations of these factors may result in the identification of autocrine/paracrine tumor cell growth inhibitory proteins for future use in clinical applications.

Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin

Angiogenesis inhibitors, such as TNP-470 and the nontoxic HPMA copolymer-TNP-470 (caplostatin), are emerging as a class of anticancer drugs. We report that TNP-470 and caplostatin inhibit vascular hyperpermeability of tumor blood vessels as well as that induced in mouse skin by different mediators. Treatment with TNP-470 or angiostatin for 3 days was sufficient to reduce permeability of tumor blood vessels, delayed-type hypersensitivity, and pulmonary edema induced by IL-2. TNP-470 also inhibited VPF/VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These results identify an activity of TNP-470, that of inhibiting vessel hyperpermeability. This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation.

Candidate genes upregulated in density dependent growth inhibition of lung cancer cells

Prognosis of lung cancer remains poor despite the recent development of new chemotherapeutic agents. Novel therapeutic strategies therefore need to be developed. The search for factors inhibiting tumor growth in a paracrine/autocrine fashion might result in a well-tolerated adjuvant tumor therapy. In this study we aimed to identify candidate genes for such inhibitors of tumor cell growth. Native and heat-inactivated supernatants of confluent, slow growing H460 tumor cell cultures and of sparse (non-confluent), fast growing H460 tumor cell cultures were tested in proliferation assays. We observed that native supernatant of confluent H460 and A549 cells contain proteins inhibiting tumor cell growth of NSCLC cell lines. Microarray gene expression analysis of sparse and confluent H460 cells exhibited overexpression of 7 candidate genes in confluent, slow growing cells. The products of these genes possess cell growth inhibitory function and also exist in the extracellular compartment. The increased expression level of these genes was verified using real-time RT-PCR analysis. Our results show that especially components of IGF pathway appear to be involved in exogenous growth inhibition of confluent cells. Further investigations of these factors may result in the identification of autocrine/paracrine tumor cell growth inhibitory proteins for future use in clinical applications.

Clinical significance of angiogenesis in gastrointestinal cancers: a target for novel prognostic and therapeutic approaches.

To review the current data on the prognostic and therapeutic implications of tumor angiogenesis in gastrointestinal cancers. Numerous studies have evaluated the prognostic value of tumor angiogenesis and the potential role of antiangiogenic therapy in various gastrointestinal cancers. A Medline literature search was conducted using "angiogenesis" or the names of various angiogenic factors in combination with the names of gastrointestinal cancers as the key words. Several studies have demonstrated a significant prognostic impact of tumor microvessel density and tumor expression of angiogenic factors, in particular vascular endothelial growth factor (VEGF), in various gastrointestinal cancers. A few studies have suggested that circulating VEGF might be a useful prognostic marker. However, results were not consistent across all studies and were limited by the retrospective nature of most studies. Antiangiogenic therapy has been shown to be effective against all common gastrointestinal cancers in preclinical studies, but currently there are few clinical data with regard to antiangiogenic therapy in gastrointestinal cancers. There is mounting evidence to suggest that assessment of tumor angiogenesis might provide a novel approach of prognostication in patients with gastrointestinal cancers. However, current results from retrospective studies need to be validated by prospective studies. Antiangiogenic therapy is a promising strategy of cancer treatment that might be particularly useful in combination therapy for unresectable cancers or as an adjuvant therapy for resectable tumors.

The effect of subcutaneous tumour implantation in a murine lung tumour model

It was hypothesized that if tumour were implanted subcutaneously within a Millipore Chamber (MPC), then this would result in an 'anti-tumour' immune response. Such an approach could have potential as an adjuvant tumour therapy when combined with surgical resection. A murine lung tumour model was used to test this hypothesis. Lung tumours were induced in 245 syngeneic mice by intraperitoneal 4-[methylnitrosamino]-1-[3 pyridyl]-1-butanone. In addition, MPCs were implanted containing either normal lung (Group A) or lung tumour (Group B). Group C had no implanted MPCs. These animals were sacrificed between 1 and 8 weeks following implantation and the stage of lung tumour development as assessed by the surface tumour count (STC) of their left lungs was compared between the different groups. The presence of CD4(+) and CD8(+) T cells in the local reactions surrounding the implanted chambers was also compared between Groups A and B at 1 week post-implantation. At 1 week, the STC was significantly lower in Group B (2.4+/-0.6) than in both Groups A (4.7+/-0.6) and C (4.9+/-0.9; P=0.02). In addition, at 1 week, there was a significantly greater proportion (%) of CD4(+) cells in the local reactions of Group B (52+/-3) than in Group A (35+/-3; P=0.001). Between 2 and 8 weeks post-implantation, there were no further significant differences in tumour development between the groups. Although the findings of an 'early' response were consistent with the hypothesized benefit of tumour implantation within MPCs, the later results have not confirmed its potential as an adjuvant therapy.

VEGF165 antisense RNA suppresses oncogenic properties of human esophageal squamous cell carcinoma.

To investigate the effect of antisense RNA to vascular endothelial growth factor165 (VEGF165) on human esophageal squamous cell carcinoma cell line EC109 and the feasibility of gene therapy for esophageal carcinoma. By using subclone technique, the full length of VEGF165 amino acid cDNA, which was cut from pGEM-3Zf+,was cloned inversely into the eukaryotic expression vector pCEP4. The recombinant plasmid pCEP-AVEGF165 was transfected into EC109 cell with lipofectamine. After a stable transfection, dot blot, enzyme-linked immunosorbent assay (ELISA),laser confocal imaging system analysis, transmission electron microscopy and flow cytometry were performed to determine the biological characteristics of EC109 cell line before and after transfection in vitro and whether there was a reversion in the tumorigenic properties of the EC109 cell in vitro. The eukaryotic expression vector pCEP-AVEGF165 was successfully constructed and transfected into EC109 cells. The expression of VEGF165 was significantly decreased in the transfected cells while the biological characteristics of the cells were not influenced by the expression of antisense gene. The tumorigenic and angiogenic capabilities were greatly reduced in nude mice, as demonstrated by reduced tumor end volume (820+/-112.5)mm(3) vs (7930+/-1035)mm(3) and (7850+/-950)mm(3), P<0.01) and microvessel density (average number: (8.5+/-1.2)mm(-2) vs (44.3+/-9.4)mm(-2) and (46.4+/-12.6)mm(-2), P<0.01) in comparison between experimental groups empty vector transfected group and control group. The angiogenesis and tumorigenicity of human esophageal squamous cell carcinoma were effectively inhibited by VEGF165 antisense RNA. Antisense RNA to VEGF165 can potentially be used as an adjuvant therapy for solid tumors.

Immunologic approaches to therapy for brain tumors.

Malignant brain tumors are notoriously invasive. Although surgical debulking can relieve the patient of the main mass of tumor, adjuvant treatments are needed to target the glioma cells that infiltrate through normal parenchyma as single cells or pockets of tumor cells from which recurrent tumors arise. Successful adjuvant cellular therapy of brain tumors, or activation of endogenous immune cells, requires that either cell effectors make direct contact with tumor cells or come within close proximity to them and exert an indirect effect. This review examines current clinical trials aimed at direct lysis of glioma cells and trials making gliomas more visible to the endogenous immune system.

Biological effects of natural and recombinant mistletoe lectin and an aqueous mistletoe extract on human monocytes and lymphocytes in vitro.

Mistletoe lectin is thought to constitute the active principle in extract preparations from mistletoe, which are widely used as immunomodulators in adjuvant tumor therapy. However, no study exists which compares the immunological potency of different well-defined mistletoe lectin preparations on human immune cells. Therefore, in the present study the biological effects of an aqueous mistletoe extract, standardized for mistletoe lectin I (eML), the isolated natural mistletoe lectin (nML), and the recombinant form of this lectin (rML) on human peripheral blood monocytes and lymphocytes were compared with respect to cell viability and cytokine induction. After 48-hr incubation of peripheral blood mononuclear cells (PBMC) with rML, nML, and eML, a continuous concentration-dependent decrease in cell viability was found with an IC50 of about 3 ng/ml for rML and nML and 10 ng/ml for eML, respectively. This effect also was seen when isolated lymphocytes and monocytes were separately incubated with the lectin preparations. After incubation of PBMC and isolated monocytes of 5/10 blood donors with eML, an increase in cell viability was found at lectin concentrations between 10 and 1,000 pg/ml. This effect was not seen with the pure lectin preparations nML and rML. After 48-hr incubation of PBMC with rML, nML, and eML, induction of IL-1-beta, TNF-alpha, IL-2, IL-6, and IL-10 but not IFN-gamma was measured. For IL-1-beta it could be shown that cytokine induction took place at a broad lectin concentration range (0.1-100 ng/ml). Cytokine levels varied greatly in the PBMC cultures of the different blood donors. When monocytes were separately incubated with eML, nML, and rML for 48 hr, high levels of IL-1-beta were found. In contrast, in cultures of separated lymphocytes from the same donors only a minimal production of IL-1-beta and no production of IFN-gamma was found after incubation with rML, nML, and eML. It is concluded that there are quantitative differences in the immunomodulatory effects of the mistletoe lectin preparations on human monocytes and lymphocytes. Therefore, measurement of cell viability and cytokine induction may be a diagnostic laboratory tool to determine the immunological potency of various mistletoe preparations and may help to clarify the clinical benefit of therapies with these substances.

Potentiation of Tumor Necrosis Factor-α-Induced Apoptosis by Mistletoe Lectin

Mistletoe ledins (MLs) constitute the active principle in extract preparations from mistletoe, commonly used as immunomodulator in adjuvant tumor therapy. MLs, classified as type II ribosome inactivating proteins, inhibit protein synthesis. Inhibitors of protein synthesis may modify cancer cell response to tumor necrosis factor-α (TNF). In the present study, we have hypothesized that the anticancer efficacy of TNF may be potentiated by MLs. In deed, simultaneous treatment of human cervix carcinoma HeLa or breast carcinoma MCF-7 cells with MLs isolated from European or Korean mistletoe rendered them more sensitive to induction of apoptosis by TNF. The mechanism by which MLs amplify the effect of TNF may involve suppression of the survival protein synthesis.