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Constitutive activation of the extracellular signal-regulated kinase (ERK) and/or phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathways is associated with neoplastic transformation of a variety of human tumor cells. Treatment of such tumor cells with agents that specifically inhibit the activity of mitogen-activated protein kinase/ERK kinase (MEK) or PI3K completely suppresses their proliferation. However, treatment of cells with these inhibitors leads to only a modest increase in apoptotic cell death. Efficient induction of apoptosis is essential for the development of effective cancer chemotherapy. Therefore, we have examined whether specific blockade of these two signaling pathways affects the efficacy of the induction of apoptosis by various anti-cancer agents in tumor cells. We found that MEK inhibitors markedly enhance the efficacy of histone deacetylase inhibitors to induce the generation of reactive oxygen species and apoptosis. This effect was only observed in tumor cells in which the ERK pathway was constitutively activated. Furthermore, we found that PI3K inhibitors selectively and markedly enhanced the efficacy of the induction of apoptosis by doxorubicin. This latter effect was only detected in tumor cells in which the PI3K/Akt pathway was constitutively activated and in which the p53 pathway was functional. These combination treatments provide an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway or PI3K/Akt pathway is constitutively activated. This review gives an overview of the development of new targeted molecular strategies for cancer therapy based on the suppression of the activity of oncogenic pathways involved in the proliferation or survival of tumor cells.

The inhibitory effects of hybrid liposomes composed of lipids having a variety of head groups (zwitterionic L-alpha-dimyristoylphosphatidylcholine (DMPC), anionic L-alpha-dimyristoylphosphatidylglycerol (DMPG), and cationic 1,2-dimyristoyl-3-trimethylammonium propane (DMTAP)) and polyoxyethylene (10) dodecyl ether (C12(EO)10) on the growth of tumor cells (human lung carcinoma (RERF-LC-OK), human hepatoma (Hep-G2), human stomach tumor (GT3TKB)) in vitro were examined. The hybrid liposomes of DMPC/10 mol% C12(EO)10 and DMPG/10 mol% C12(EO)10 were fairly more effective for inhibiting the growth of all tumor cells employed in this study as compared with liposomes (DMPC and DMPG) or micelles (C12(EO)10). Especially, it is attractive that the highly specific inhibitory effect of the hybrid liposomes of DMPG/10 mol% C12(EO)10 without any antitumor drugs on the growth of RERF-LC-OK and GT3TKB was obtained for the first time.

Trichostatins and trapoxins, structurally unrelated microbial metabolites, are specific inhibitors of histone deacetylases. Radicicol inhibits Src family protein-tyrosine kinases. Recently, these agents were found to induce morphological reversion and enhanced expression of gelsolin, an actin regulatory protein, in a variety of transformed cells. Microinjection of an anti-gelsolin antibody that neutralizes the gelsolin function caused inhibition of the morphological change, suggesting that gelsolin expression is associated with the suppression of transformation.

The influence of surgery and anesthesia on aspects of malignant tumor has received considerable attention in recent years. It is suggested that in vitro studies, clinically available anesthetics, such as intravenous anesthetics, local anesthetics and opioids have, more or less, possible antitumor potential against human malignant tumor cells. Although natural killer (NK) cells play an important role in tumor and metastasis surveillance, the reported effects of the anesthetics on the NK cell activity in human are controversial. Animal studies indicate that the neuroendocrine stress response to the surgery suppresses the immune function, particularly NK cell cytotoxicity, and increases the metastatic burden under inhalational anesthesia alone. Moreover, animal studies indicate that the addition of spinal block and optimum postoperative analgesia independently reduce the metastatic burden by blocking the stress response under inhalational anesthesia alone. Considering inconclusive results, especially in human, about evaluating the influence of anesthetics on malignant tumor, further studies in basic and clinical settings are required to study the effects of anesthetics on malignant tumor.

RNA interference (RNAi) is a posttranscriptional gene-silencing event in which short double-stranded RNA (siRNA) degrades target mRNA. Because of its potent and highly specific gene-silencing effect, RNAi is expected to be used in the treatment of various diseases. Cancer is one of the major targets of RNAi-based therapy, because silencing oncogenes or other genes contributing to tumor progression can be target genes for RNAi. The delivery of RNAi effector to target cells is one of the key factors determining therapeutic efficacy, because gene silencing is limited to cells reached by RNAi effectors. Tumor cell lines stably expressing reporter genes were confirmed to be effective in sensitively and quantitatively evaluating RNAi effects in tumor cells in vitro and in vivo. Quantitative analyses of the gene-silencing effect revealed that short-hairpin RNA expressing plasmid DNA (pshRNA) has more durable effects than siRNA. Intratumoral injection of RNAi effectors was effective in suppressing target gene expression in tumor cells, and silencing of beta-catenin or hypoxia-inducible factor-1alpha (HIF-1alpha) significantly inhibited tumor growth. RNAi effectors were successfully delivered to tumor cells colonizing the liver through the vascular route. We found that tumor-bearing liver showed elevated HIF-1alpha expression in the cells, and the silencing of the expression in normal liver cells is also effective in inhibiting metastatic tumor growth. These results indicate the possibility of RNAi-based cancer therapy.

HspBP1 was originally identified and characterized as a novel Hsp70/Hsc70-interacting protein that inhibited the Hsp70/Hsc70 chaperone activity. In this respect, Hsps have been shown to influence cell-death pathway through the interaction with key components of the apoptotic machinery. In this report, we have examined the effect of HspBP1 overexpression on the sensitivity of tumor cells to anticancer drug-induced apoptotic response. Analysis with HspBP1 deletion mutant genes showed that C-terminus 47 amino acid residues were essential for the specific interaction of HspBP1 with Hsp70/Hsc70. Overexpression of HspBP1 induced enhanced apoptotic response against anticancer drugs, but HspBP1 lacking C-terminus 47 amino acid residues did not. These results support the notion that inhibition of the function of Hsp70 enhances the therapeutic efficacy of chemotherapy.

cDNA microarray technology permits the simultaneous measurement of the expressions of thousands of genes. The technology is now an indispensable research tool in molecular biology, and the challenge is its development and usage as clinical diagnostic tools. cDNA microarray can be used to identify gene expression profiles in tumor cells which correlate strongly with the treatment responsiveness such as drug resistance and clinical outcome of the disease despite similar phenotypes. For the introduction of cDNA microarray into laboratory examination, many issues need to be resolved. Design of a diagnostic array must be developed with defined sequences based on interpretation of huge quantities of data from experimental arrays to predict treatment responsiveness. Assay quality must be improved in terms of detection sensitivity, reproducibility, and linear dynamic range for RNA quantitation. Generally available instruments, which are much less expensive and more practical, need to be developed. Along with the improvement of the assay as a laboratory examination method, cDNA microarray will facilitate the integration of diagnosis and therapeutics, and the introduction of individual medicines.

Recent advances in the detection of both isolated tumor cells and micrometastases in distant organs by means of immunocytochemical and molecular biological techniques have brought a new paradigm for the understanding of cancer biology. For instance, although the presence of a micrometastasis is a significant indicator of poor prognosis, it is now widely accepted that certain residual tumor cells remain dormant for a long period without any treatment. Many investigators have focused on what is different in the nature of the dormant and active tumor cells, and how microtumors can acquire the active phenotype in ectopic distant organs. In addition, information on both isolated tumor cells and micrometastases is useful not only for staging but also for considering an adjuvant treatment schedule. This review summarizes the recent clinical outcomes of the investigations of both isolated tumor cells and micrometastases.

Tumor cells show a higher glycolytic rate than normal cells. Of glycolytic enzymes, the activity of hexokinase, known as a rate limiting enzyme in glycolysis, is amazingly high in malignant tumor cells. In mammals, four isozymes of hexokinase are expressed but the question which isozyme is responsible for the high hexokinase activity observed in tumor cells was not yet clearly answered. By Northern blot analysis, we found that the type II isozyme, which is only slightly expressed in normal heart, muscle and adipose tissue, was remarkably expressed in malignant tumor cells. We next tried to understand how the expression of type II hexokinase gene is regulated in tumor cells. For this purpose, we first isolated the type II hexokinase gene and characterized its structural features. We further investigated the regulatory mechanisms of the expression of type II hexokinase in tumor cells. Results indicate the potential involvement of a serum responsive factor in the regulation of the expression of type II hexokinase in tumor cells. In addition to the remarkable expression, binding of the type II hexokinase to mitochondria is another characteristic of tumor cells, however, the physiological meaning of hexokinase binding to mitochondria was not yet fully understood. Our results clearly showed that the mitochondria-bound hexokinase utilize mitochondrially generated ATP more preferentially under normal conditions. However, when the rate of extramitochondrial ATP generating system (glycolysis) exceed that of mitochondrial ATP generating system (oxidative phosphorylation), the mitochondria-bound hexokinase utilize extramitochondrial ATP. This result indicates that the hexokinase binding enables a cross talk between oxidative phosphorylation and glycolysis.

To estimate the relationship between the expression of thymidylate synthase (TS) in tumors and clinical response and prognosis in cancer patients treated with 5-fluorouracil (5-FU), the anti-TS polyclonal antibody against recombinant human TS (rhTS) was prepared and purified. At the initial stage, we attempted to clarify the relationships between the expression of TS protein and the cytotoxicity of 5-FU in established human cancer cells in vitro. Our purified anti-TS antibody was demonstrated to react specifically with intracellular TS as revealed by western blot analysis and immunohistochemistry. Furthermore, it was revealed that the expression of TS proteins correlated with cytotoxicity (IC50 value) of 5-FU against human colorectal tumor cells, both sensitive and those with acquired resistance to 5-fluoropyrimidines, and other cancer cell lines as well. These results suggest that our anti-TS polyclonal antibody (IgG) is suitable for clinical prospective and retrospective studies on TS expression in various cancers as a prognostic factor and 5-FU response-predicting parameter.

Recent studies have indicated that different patterns of latent viral gene expression were observed in a number of Epstein-Barr virus (EBV)-positive tumors. Among the latent viral genes, EBERs and EBNA1 genes are commonly expressed in EBV-associated tumor cells. Out of eight EBERs-negative NPC cases, four were shown to be EBV DNA-positive by in situ PCR which could detect one copy of integrated EBV genome per cell. EBER1-expressing cells in paraffin-embedded sections of T-cell lymphoma cases were detected in about 44% of T-cell lymphoma cases while 66% of the cases showed positive for EBNA1 mRNA by in situ hybridization (ISH) with EBNA1 specific RNA probe, indicating the presence of T-cell lymphomas expressing EBNA1 mRNA but not EBER1. LMP1 mRNA was expressed in 53% of the cases which were strongly associated with aggressive clinical course. Thus, the introduction of DNA-RNA ISH for detection of EBNA1 mRNA and in situ PCR for detection of latent EBV DNA could provide a unique tool for the detection of latently infected cells in histological sections.

While not all circulating tumor cells survive, one could postulate that patients with circulating tumor cells might be candidates for adjuvant chemotherapy because of the risk of relapse. Recently, reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of circulating tumor cells has been suggested as a potential technique for staging of cancer. In malignant melanoma, the detection of circulating melanoma cells by tyrosinase RT-PCR correlated with the clinical stage of patients and was an independent prognostic factor for recurrence. A strong association was found between the detection of neuroblastoma cells in circulation by tyrosine hydroxylase RT-PCR with bone marrow micrometastasis. This method may be of use to identify early signs of relapse in disease-free patients. In prostatic cancer, the frequency of positivity for detection of circulating tumor cells in peripheral blood by PSA RT-PCR increased with tumor stages but a significant proportion of patients with metastatic disease were negative. The prognostic significance of the detection of tumor cell in blood in other epithelial tumors is not established and will require further long-term follow-up study.

Tumor cells have to degrade extracellular matrix components to invade surrounding tissue and to form metastatic colonies at distant organs. Matrix metalloproteinases are the enzymes that can degrade various types of native collagens and glycoproteins. In this study, we demonstrated the roles of matrix metalloproteinases in metastatic colony formation in chick embryo by transfecting TIMP-1 gene into a metastatic gastric cancer cell line, KKLS. The mechanism regulating expression of one of the type IV collagenases, MMP-9, was also studied using the promoter region of the gene.

Chromosomal changes plays an important role in malignant transformation. Generally, the process of karyotype instability with grows aneuploidy occurs in tumor. But it is very difficult to obtained Flow karyotype from tumor cells. There are many technical problem in the analysis of chromosomes aberration in tumor cells. Problem is technical procedure of isolation from metaphase chromosomes. It is important to choice of swelling buffer and treatment times. Such technic affect for Flow karyotype pattern. We try to obtained Flow karyotype from chinese hamster cell and V-79 cells and we reported a recent new techniques of cell preparation and chromosomes suspension.

We investigated the effect of recombinant human tumor necrosis factor (rhTNF) on hydroxyl radical production by established cell lines in vitro, and its implication in the killing of tumor cells by rhTNF. During incubation of TNF sensitive mouse tumorigenic fibroblast L-M cells in the presence of rhTNF, hydroxyl radical production detected by the evolution of methane gas from dimethyl sulfoxide increased gradually, at 18 hours reached 1.8 times of that in the absence of rhTNF. This increase of hydroxyl radical production was dependent on the concentration of rhTNF. The addition of iron chelator 2,2'-bipyridine which inhibits iron catalized Fenton reaction and inhibits hydroxyl radical generation, suppressed both the increase of hydroxyl radical production and the cytotoxicity induced by rhTNF. The increase of hydroxyl radical production stimulated by rhTNF was also detected in TNF sensitive human myosarcoma derived KYM cells as well as in L-M cells, but no change was detected in TNF insensitive human embryonic lung fibroblast HEL cells. These results suggest that rhTNF induced increase of hydroxyl radical production may play a significant role in the mechanism of tumor cell killing by rhTNF.

Cancer is the most common cause of death in Japan. Fundamental and clinical studies on cancer were conducted from the viewpoint of Western medicine so far. However, a sustained complete remission has not been achieved yet. In order to alleviate the side effects of anticancer drugs, some traditional herbal medicines (Kampo medicines) have been prescribed to cancer patients. We have been studying on antitumor substances in medicinal herbs and found an antitumor medicinal herb named Rhus verniciflua (lacquer, Urushi in Japanese). To investigate the antitumor effect in vitro, a plant extract mixture was prepared from six medicinal herbs containing lacquer. The plant extract mixture containing lacquer (Rv-PEM) inhibited the proliferation of several mouse and human tumor cell lines. Rv-PEM had more potent inhibitory effect on the proliferation of human leukemia cell lines (MOLT-3, KG-1) than on other tumor cell lines. The IC50 values of Rv-PEM on MOLT-3 and KG-1 cells were 0.208 and 0.293 mg/mL, respectively. After treating Rv-PEM to the tumor cells, DNA fragmentation and Caspase-3 and -9 activity increased in the treated cells. The mechanisms of the inhibitory proliferation activity of Rv-PEM would involve apoptosis of human leukemia cells (MOLT-3, KG-1, K-562) by the mitochondrial pathway.

Treatment of advanced SCLC remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative life span strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the small-cell lung cancers were examined in a previous study. In this study, we turned the expression of hTERT by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anti-cancer effect in vitro and in vivo. As a further enhancement the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3, and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoter-based CRAds may be a potentially effective strategy for cancer treatment.

Differently from target-based anticancer drugs, molecular mechanisms of actions are not well-known in many of the classical antineoplastic agents. With the exception of vinca alkaloids and taxanes, all of the classical antineoplastic agents work on DNA metabolism in cells and can therefore be categorised as 'DNA metabolism inhibitor'. Cellular sensitivity against these drugs largely depends on various activities in DNA metabolism, particularly in DNA repair. However, DNA repair as a determinant of drug sensitivity had long received little attention. DNA mismatch repair (MMR) is now regarded as an important determinant to alter cellular sensitivities against various drugs including fluoropyrimidines, platinum compounds and topoisomerase inhibitors. However, molecular mechanisms of this connection are still unknown. In particular, the relationship between MMR and 5-fluorouraci (l 5-FU) sensitivity is now being approached by examining the tumour MMR status and clinical outcomes in colorectal cancer patients treated with 5-FU-based adjuvant chemotherapies. However, reported results lack consistency, possibly due to the methodological problems in assays used to determine the MMR status. On the other hand, nucleotide excision repair (NER) is also regarded as an important determinant of cisplatin (CDDP) sensitivity. Expression of ERCC 1, a component of this complex multi-protein system, has been reported to be a determinant of prognosis in CDDP-treated non-small-cell lung cancer patients. In order to establish the significance of DNA repair as a determinant of tumour chemosensitivity, further basic studies, particularly ones approached from biochemical viewpoints, are required. Clinical studies supported by accurate assay techniques are also needed.

Rhamnose-binding lectins are widely found in fish eggs. However, their biologic effects on cultured cells are still unknown. Since catfish (Silurus asotus) egg lectin (SAL) bound to globotriaosylceramide (Gb3) expressed on the surface of cells, we analyzed the relationship between Gb3 expression and SAL binding in tumor cell lines using Raji, Daudi, ACHN, P388, and K562 cells. Gb3 was highly expressed on Raji cells but not on K562 cells. SAL bound abundantly to Raji cells but not to K562 cells, and SAL binding depended on the amount of Gb3 on the cell surface. SAL caused a reduction in cell size and increased annexin-V binding to and propidium iodide (PI) incorporation into Raji cells. Although this effect on Raji cells might represent damage at the late apoptosis or necrosis stage, SAL-treated Raji cells remained alive. Thus SAL enhanced PI incorporation into Raji cells without induction of cell death. We examined whether the effects of chemotherapeutic agent(s) are influenced by SAL. SAL increased the incorporation of doxorubicin (Dox) into Raji cells and consequently enhanced the cytotoxic effects of Dox. These results indicate that SAL may induce cell permeability without cytotoxity.

Possible pathways of intracellular phosphorylation of 5-fluorouracil (5-FU) in human cancer cells were investigated in vitro and in vivo. We used two inhibitors which regulate the anabolism of 5-FU for the purpose of elucidation of its pathways; one is oxonic acid (Oxo), an inhibitor of orotate phosphoribosyltransferase (OPRTase), catalizing a formation of FUMP from 5-FU, and another is 2, 6-dihydroxypyridine (DP), an inhibitor of uracil ribosyltransferase which catalizes a conversion of 5-FU to 5-fluorouridine. Although the pathway of 5-FU phosphorylation in murine tumor cells was varied, about 80% of human cancer cells tested were found to utilize the first pathway in which 5-FU was converted to FUMP by OPRTase. Thus, the phosphorylation of 5-FU via the first pathway was markedly inhibited by Oxo in 4 strains of 5 gastric cancer cells, 7 of 8 colorectal cancer cells and 3 of 4 lung cancer cells. In xenografts of human gastric and colorectal adenocarcinoma in which 5-FU phosphorylation is regulated by Oxo in vitro, the production of 5-fluoronucleotides and its incorporation into RNA after iv administration of 5-FU significantly decreased by co-administration of Oxo, suggesting that the nature of an anabolic pathway of 5-FU in the tumor cells in vitro reflects in vivo behavior. We also confirmed that the phosphoribosylpyrophosphate level in tumor cells was importantly related to determination of the metabolic pathway of 5-FU. These results would suggest that possible modulation of 5-FU lies on the augmentation of 5-FU efficacy.

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25 (OH)2D3] has antiproliferative, differentiation and apoptosis-inducing effects on many malignant cells. These properties have raised the possibility of its use as a therapeutic agent in cancer. Our recent studies using stereoisomers of the A-ring of monohydroxylated 19-nor or 2-methyl substituted 1 alpha,25 (OH)2D3 have clearly demonstrated that the A-ring analogs that contain 1 alpha-hydroxy or 3 beta-hydroxy group are potent inducers of HL-60 cell differentiation. In contrast, the A-ring analogs that contain 1 beta-hydroxy or 3 alpha-hydroxy group are potent stimulators of HL-60 cell apoptosis. It was interesting to note that the analogs could induce differentiation or apoptosis of HL-60 cells on the basis of the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring. To further elucidate the possible roles of both the hydroxy groups in regulating cell differentiation and apoptosis, we have synthesized all possible diastereomers of the A-ring of 1 alpha,25 (OH)2D3 and examined their molecular mechanism of differentiation and apoptosis-inducing actions of HL-60 cells in vitro. This study shows that differentiation and apoptosis of HL-60 cells are strictly controlled by the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring of 1 alpha,25 (OH)2D3, and the proteins responsible for the regulation of cell cycle and mitochondrial membrane potential are the major targets of 1 alpha,25 (OH)2D3 analogs. These findings provide useful information not only for structure-function studies of 1 alpha,25 (OH)2D3 analogs but also for the development of therapeutic agents for the treatment of cancer.

Apoptosis has recently been considered to be a predictor of tumor response or outcome following chemotherapy or radiotherapy. Although apoptosis clearly occurs in the very early stages following such treatments, it is unclear whether its frequency correlates with the likelihood of tumor cure following radiotherapy, especially in solid tumors, where the major mode of cell death is necrosis. This review discuses the relationship between apoptotic activity and radiosensitivity or tumor response from various points of view, including experimental systems and clinical conditions.

ErbB-2, a member of the epidermal growth factor(EGF) receptor tyrosine kinase family, is often overexpressed and/or amplified in breast, ovarian and gastric cancers, and other malignancies. ErbB-2 is a candidate as one of the best target molecules for cancer therapy. Many anti-ErbB-2 monoclonal antibodies(MoAbs) have been developed. An inhibitory humanized MoAb shows clinical responses in some breast cancer patients, both with MoAb alone and in combination with Cisplatinum or other anti-cancer drugs. A mouse-human chimeric anti-ErbB-2 MoAb CH401 was established and characterized in our laboratory. CH401 is able to kill cancer cells overexpressing ErbB-2 both in vitro and in vivo. The analysis of this tumor growth inhibition by CH401 made it clear that the cytotoxicity was induced by apoptosis. These results may suggest that CH401 has a therapeutic potential for ErbB-2 overexpressing cancers. This approach may be particularly valuable as a new type of cancer therapy.

Many glycoproteins which are produced by tumor cells and released into serum and urine, are useful for the diagnosis and prognosis of tumors. This review article describes the representative glycoproteins in this field and includes details about their carbohydrate moieties which have been clarified in recent years.

Dual parameter analysis of FCM using rhodamine 123 (R 123) and propidium iodide (PI) has made it easy to estimate cell viability. PI stains only dead cells, whereas R 123 accumulates in the mitochondria of living cells which remain unstained by PI. Therefore the combination of R 123 and PI provides a more accurate estimation of cell viability than the conventional methods of dye exclusion. Cell viability has been estimated by this method in HeLa cells treated with adriamycin in vitro. The usefulness of this analysis is suggested for the evaluation of the effect of anticancer drugs on tumor cells.

Effector lymphocytes cytotoxic to autologous tumor cells consist of heterogeneous populations. In this communication, we have presented the results of experiments, in which these heterogeneous effector cells were classified based on their surface markers and modes of differentiation depending upon culture conditions. NK cells with a typical phenotype of CD2+ 3-16+ were one of major populations, which could respond to IL-2 and be differentiated into lymphokine activated killer (LAK) cells. LAK cells were also induced from a CD3+4-8- T cell subset by IL-2 stimulation. Effector cells with a phenotype of CD2+ 3-4-8-16-, which may belong to the T cells at early stages of differentiation, could also be induced by stimulation of immunoadjuvants. Finally, it was shown that the effector cells with a typical phenotype of cytotoxic T lymphocytes, CD3+4-8+16-, and a non-MHC-restricted cytotoxicity were induced by IL-2 in the tumor infiltrating lymphocytes.

Recently, it has been shown clearly that various tumor cells can be induced by differentiation inducers including biological response modifiers, synthetic chemicals and conventional anticancer drugs to differentiate terminally both in vitro and in vivo into cells with normal characteristics. On differentiation, the cells cease to proliferate and lose their transplantability in either nude mice or syngeneic animals. Furthermore, prolongation by the differentiation inducers of survival times of animals inoculated with various tumors was confirmed. These findings suggest that induction of terminal cell differentiation by differentiation inducers is another approach to tumor therapy, that is "differentiation therapy" of tumors. In this review, recent results of basic and clinical studies on the differentiation therapy of tumors are described. The problems and perspectives of differentiation therapy are also discussed.