A new spontaneous liver metastasis model from LMFS tumor, a retroperitoneal sarcoma of BALB/c mouse origin, was reported. After a subcutaneous injection of LMFS cells in the footpad, amputation of the leg was performed every 5 days from day 5 to day 20, and mice were killed at day 25 under anesthesia. The LMFS cells proliferated at the inoculation site (100% take), and all mice operated after day 15 had metastatic nodules spontaneously in the liver. Local recurrence was not observed in any cases. Liver weight was correlated with tumor growth in the liver. The combination therapy of operation and HCFU was examined in comparison with the footpad injection model. The foot on the injection side was amputated on day 12 with or without HCFU administration, and mice were sacrificed on day 33 under anesthesia. Histological liver metastases were as follows: 1. no treatments: 100%; 2. early phase chemotherapy without operation: 80%; 3. operation without chemotherapy: 80%; 4. postoperative chemotherapy: 20%; 5. preoperative chemotherapy: 40%; and 6. late phase chemotherapy without operation: 100%. These results indicate that operation with chemotherapy is the most useful treatment for liver metastases. Using this liver metastatic model, we are investigating a new combination therapy of operation and anti-cancer drugs for liver metastases.

Tin generates a wide variety of biological activities deriving from its chemical character. In this article, the biological activities of tin compounds are reviewed with a focus on the connection with immunity. The table of contents is as follows: Introduction, 1. Inorganic Tin and Immunity, 2. Organic Tin and Immunity, 2.1. Immunotoxicity, 2.1.1. Immunosuppression, 2.1.2. Thymus atrophy, 2.1.3. Changes in the membrane surface antigens of T cells, 2.2. Antitumor activity, 2.3. Anti-inflammatory action, 2.4. Tolerance manifestation of thymus atrophy, 3. Cellular and Biochemical Aspects of the Activity Manifestation, 3.1. Intracellular distribution of organotins 3.2. Effects on structure and function of Golgi apparatus and endoplasmic reticulum, 3.3. Effects on physical properties of phospholipid membrane, 3.4. Suppressive effects on cell proliferation system, 3.5. Consideration, Conclusion. To sum up this article, tin compounds (especially organotin compounds) act mainly on cellular immune systems and the mechanism appears to be due to their hydrophobicity-dependent intracellular distribution and their action on the phospholipid metabolism including the inhibition of intracellular phospholipid transport between organelles through an impairment of the structure and functions of the Golgi apparatus and the endoplasmic reticulum (ER), and the consequent inhibition of the membrane-mediated signal transduction system leading to DNA synthesis via phospholipid turnover and Ca2+ mobilization.

Cardiac function was evaluated in 53 elderly patients with hematologic malignancies who were being treated with doxorubicin (DXR). The left ventricular ejection fraction was measured by radionuclide angiocardiography, the washout rate by 123I-MIBG myocardial SPECT, the extent and severity scores by 123I-BMIPP myocardial SPECT, and the frequency of premature ventricular contractions by Holter electrocardiography. 1) In some patients, both the washout rate and the extent and severity scores were abnormally high before treatment. 2) Because the washout rate correlated with the total dose of DXR, it may be an early indicator of cardiac sympathetic nervous dysfunction. 3) The left ventricular ejection fraction correlated with the extent and severity scores, but not with the washout rate or with the frequency of premature ventricular contractions. 4) The washout rate correlated with the frequency of premature ventricular contractions. These data show that elderly patients had abnormal cardiac function even before treatment with DXR; that cardiac sympathetic dysfunction and cardiac mitochondrial dysfunction developed at total DXR doses of 250 to 300 mg/m2 or higher; and that the left ventricular ejection fraction was less than or equal to 50% in many patients. Consequently, when DXR is used to treat elderly patients, multimodal evaluation of cardiac function is necessary to detect cardiotoxicity and to determine the optimal total dose and the optimal dosage.

Hypopharyngeal squamous cell carcinomas (HPC) has an extremely poor prognosis. Characteristics of cell lines of head and neck squamous cell carcinomas including HPC were studied by various methods, e.g., chemosensitivity test and the immunohistochemistry staining method, to determine whether this poor prognosis is due to the biological behavior of this cancer. An HPC cell line was found to be resistant to anti tumor drugs, i.e., PEP, MTX and CPM and moderately sensitive to CDDP, 5-FU and ADM. Thermoresistance to hyperthermatic treatment and weak expression of ICAM-1 on the HPC cell line were observed. DNA synthesis by the HPC cell line was induced by stimulation with a low concentration of EGF and the amount of EGFR on these HPC cells was very high. In addition, cyclinD1 overexpression was found in the HPC cell line. Based on the above findings, further analysis of hypopharyngeal carcinoma cells and the development of a new treatment modality to control tumor growth and metastatic factors influencing the poor outcome are necessary to improve the prognosis of this cancer.

Because about half of patients with cancer could not be cured by the present standard therapy, new effective anticancer agents should be developed and introduced at the clinical level. However, there are several important and specific issues from scientific, medical, statistical, and ethical viewpoints in the design and conducting of phase I clinical trials of new anticancer agents. Clinical safety data management is critically important in phase I clinical trials. Phase I clinical trials are vastly different from phase II or III clinical trials in terms of these issues. This paper discusses issues of early anticancer drug development to be solved or improved.

The elimination of tumor cells by cytotoxic T lymphocytes (CTLs) is, in part, executed by inducing apoptosis through the cell surface antigen Fas on the target cells. There are many cancer cells that resist Fas-mediated apoptosis. To elucidate the mechanism of this resistance is very important to understand the process of tumor development. We focused on FAP-1 (Fas-associated phos phatase-1), a negative regulator of Fas-mediated apoptosis. The expression of FAP-1 was detected in many colon cancer cell lines. On the other hand no FAP-1 expression was detected in the normal colon tissue. We have found that the tri-peptide of Fas C-terminus inhibited the binding of Fas and FAP-1 in vitro. Microinjection of the tri peptide (Ac SLV) could induce Fas-mediated apoptosis in the DLD 1 human colon cancer cell line that was resistant to anti-Fas-antibody. These findings suggest that the interaction of Fas and FAP-1 has a very important role in Fas-mediated apoptosis signal transduction. The inhibition of the Fas/ FAP-1 binding will provide a good target to develop anti-cancer drugs.

Many antineoplastic drugs and cytotoxic irradiation induce apoptosis in cancer cells. ICE and ICE-like proteases play important roles in drug-induced apoptosis of cancer cells. We evaluated the cellular factors affecting susceptibility to apoptosis using gene-transfected cells. Introduction of bcl 2 gene into human small cell lung cancer cells conferred resistance to mitomycin C and irinotecan. DNA fragmentation was reduced in these cells. These results indicate apoptosis is one of the mechanisms of cell death caused by some antineoplastic drugs. Investigations are ongoing to elucidate the contribution of the Bcl 2 family proteins to antineoplastic drug induced apoptosis. Wild type p53-transfected cancer cells were sensitive to anticancer drugs. On the other hand, p53-depleted cells were reported to be more sensitive to taxanes than p53-proficient cells. Introduction of Rb gene and p16-gene enhanced cytotoxicity of taxanes and topoisomerase I inhibitors, respectively. In clinical studies, patients of non small cell lung cancer with high expression of Bcl-2 were reported to show longer survival than patients with lower expression. However, this result may be confusing because Bcl-2 reduced the efficacy of antineoplastic drugs. Further evaluation is required to determine the cellular proteins serving as markers for treatment efficacy or prognosis.

Some chemotherapeutic agents, as well as TNF and Fas, induce apoptotic cell death in tumor cells, but the cellular components involved in the process have not yet been identified. Interleukin 1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in nematode Caenorhabditis elegans. We found that a selective inhibitor of ICE/ced 3 family proteases, benzyloxycarbonyl Asp CH2OC(O) 2 6,-dichlorobenzene (Z-Asp-CH2-DCB). completely blocked the apoptotic cell death of human leukemia cells caused by etoposide, camptothecin, 1-beta-D-arabinofuranosyl cytosine (Ara-C) and adriamycin. Moreover, in antitumor agent-treated U937 cells, an ICE-like (CPP32-like) protease was strongly activated. These results indicate that ICE/ ced 3 family proteases are involved in antitumor agent-induced apoptosis. Activation of ICE family proteases plays a key role in apoptosis. However, the subsequent mechanisms resulting in apoptosis are largely unknown. We identified actin as a substrate of ICE family proteases. Cleavage of actin and other substrate proteins by ICE family proteases could be critical in the ongoing process of antitumor agent-induced apoptosis in tumor cells.

Human somatic cells gradually lose their telomeric repeats each cell division, and when they become critically shortened, stop dividing. On the other hand, in immortal cancer cells and germline cells, telomerase, a ribonucleoprotein which can compensate for the loss of telomeric repeats synthesizing telomeric DNA onto chromosomal ends, is activated and the telomere lengths are stabilized. Thus, telomere length and telomerase activity are believed to be characteristic indicators of cell proliferation and cell immortality, and inhibition of telomerase activity is expected to be a new strategy of anti-cancer therapy.

During the metastatic cascade, a tumor cell passes through several connective tissue barriers which consist of various adhesive molecules, such as fibronectin, laminin, collagens, and other glucoproteins and proteoglycans. Tumor invasion is a complex process involving cell adhesion, motility (migration), and the degradation of tissue barriers caused by the different proteases secreted by tumor cells. Therefore, understanding the invasion mechanism and the control mechanisms of the invasive properties of tumor cells may help in the development of anti-metastatic and anti-invasive therapies. We here focused our attention on the functional molecules involved in the invasive process as targets to control tumor metastasis, and screened the inhibitors of tumor invasion into basement membranes.

Aberrant angiogenesis is closely involved in invasion/metastasis as well as enlargement of tumor. One recent highlight is to develop anti angiogenic drugs by targeting tumor angiogenesis. Here we describe how tumor angiogenesis is regulated and also recent topics related to angiogenic drug in clinical trials.

We analyzed the effect of PLC inhibitor (PCI) peptides in their growth and cell cycle. N-Myristoylated PCI peptide, myr-PCI, originally developed based on the PCI sequence of PLC-gamma 2, inhibited activity of purified PLC isoforms in vitro. When myr-PCI was added to KMS-4 and KMS-8 cells, both derived from familial adenomatous polyposis patients, it suppressed the production of inositol trisphosphate, DNA synthesis, and cell growth, all of which were induced by serum in both KMS 4 and KMS 8 cells. Flow cytometry analysis with propidium iodide labelling revealed marked decreases in the percentage of KMS 8 cells in S phase and increases in G0, G1 by the addition of myr PCI. These results indicate that the activation of PLC is essential for growth and transformed properties of these colorectal carcinoma cells, and also that PLC inhibitors could be an anti-tumor drug for some cases.

Posttranslational farnesylation by farnesyltransferase (FTase) is critical for the function of ras oncogene product and FTase has attracted attention as the new target of anticancer agents. B956 and B1352, obtained from the screening of CAAX analog inhibitors of FTase, induced flat reversion and inhibited the anchorage independent growth of ras transformant and ras mutated human tumor cell lines through the inhibition of posttranslational modification of ras p21. Inhibition of tumor growth in vivo was caused by inhibition of ras processing. Methyl ester prodrug of B956 and B1352 showed antitumor activity in ras mutated human tumor xenograft model. FTase inhibitor has the potential to be developed as therapy for ras mutated human tumors.

A 21-year-old Japanese woman was referred to our hospital because of severe anemia and thrombocytopenia. Bone marrow aspiration showed a hypercellular marrow with 91.5% promyelocytes. Cytochemical study and surface marker a diagnosis of acute promyelocytic leukemia. Because leukocyte count elevated, she was treated with all-trans retinoic acid (ATRA) after conventional chemotherapy. After 11 days of ATRA therapy, the patient started to develop severe headache, nausea and diplopia. Ophthalmologic examination revealed bilateral papilledema. Computed tomography and magnetic resonance imaging of the head showed no intracranial lesion. ATRA was discontinued because it was suspected to cause intracranial hypertension. Her symptoms were relieved and patilledema improved gradually. ATRA is safe and well-tolerated, if the retinoic acid syndrome can be prevented or managed. As the tolerable dose of ATRA in adults is higher than that in children, the side effects tend to occur in children. In Japan, only two childhood cases of intracranial hypertension during ATRA therapy have been reported. We must remember the possibility of intracranial hypertension during ATRA therapy, even in adults.

Late Phase II clinical study with bropirimine (U-54461S), a novel oral antitumor agent that has interferon inducing and anti-proliferative activities, was conducted in patients with bladder CIS at 38 institutions nationwide. To investigate the efficacy and safety of the treatment, bropirimine was administered to the patients at the dose of 750 mg every two hours, three times a day, for three consecutive days with four-day drug withdrawal, based on the results of the preceding clinical studies up to early phase II. Among the 48 patients registered, 41 patients were evaluable for antitumor efficacy. Complete response (CR) was observed in 17 of them, no change (NC) in 18 patients, and progressive disease (PD) in 6 patients; so the efficacy rate was 41.5%. Classified by patient background, the efficacy rates were 58.3% (7/12) in patients with primary bladder CIS, 34.5% (10/29) in those with secondary bladder CIS, 45.5% (10/22) in those with Grade 3, and 23.8% (5/21) in those previously given chemotherapeutic agents or BCG by intravesical or other routes. Adverse drug reactions frequently observed were influenza-like symptoms such as fever and generalized malaise and gastrointestinal symptoms like anorexia and nausea/vomiting; these symptoms were all Grade 2 or milder. Abnormalities in laboratory tests, such as an elevation in GOT/GPT, neutropenia, and leukopenia were observed. These adverse effects were all tolerated by the patients. From the above results, bropirimine was considered to be a useful oral agent for the treatment of bladder CIS.

Early Phase II clinical studies with bropirimine (U-54461S) having interferon (IFN) inducing and direct antiproliferative activities were conducted in patients with various solid tumors or hematologic neoplasm at 34 institutions nationwide. To investigate the safety and efficacy of the treatment, bropirimine was orally administered to the patients at the dose of 1g every two hours, three times a day for three consecutive days with a four day drug-free interval. Among the 65 patients registered, 60 patients were eligible and 44 patients completed bropirimine treatment in accordance with the respective protocols. Complete response (CR) was observed in 7 cases, and partial response (PR) was observed in 4 cases, so the efficacy rate was 25.0% (7 CRs + 4 PRs/44). Classified by target tumors, the efficacy rates were 12.9% (6 CRs/14) in bladder CIS, 33.3% 1 CR/3) in superficial bladder cancer. 11.1% 1 PR/9) in renal cell carcinoma, and 42.9% (3 PRs/7) in malignant lymphoma, respectively. Adverse drug reactions frequently observed were influenza-like symptoms such as fever (60.0%) and generalized malaise (21.7%), gastrointestinal symptoms like anorexia (56.7%) and nausea/vomiting (43.3%), and adverse effects on the circulatory system such as tachycardia (15.0%) and abnormalities in ECG (11.7%). Most of these symptoms were relieved or improved. Abnormalities in laboratory tests observed frequently were adverse effects on the liver such as elevations in GPT (33.3%), in GOT (31.7%), and in LDH (18.3%) or on the blood system like a decrease in RBC (18.3%), leukopenia (26.7%), or neutropenia (25.0%). In conclusion, bropirimine treatment proved to be effective for bladder CIS in particular, suggesting that it will be promising for use in the treatment of the disease.

Drug-induced parkinsonism(DIP) is at present the second most frequent cause of parkinsonism next to idiopathic Parkinson's disease(PD) in Japan. The ratio of the incidence of DIP to PD has been reported to be between 1:2 and 1:5, which varied at the period surveyed. The most frequent causative drugs were calcium-blocking agents, flunarizine and cinnarizine in 1980s, and they have been replaced in recent years by benzamide derivatives with antipsychotic, antiemetic or prokinetic actions, sulpiride, tiapride and metoclopraramide. The clinical features of DIP are similar to those of PD except for rather rapid progression of the symptoms. Careful neurological examination and check of all drugs the patient has taken are important for correct diagnosis. Most causative drugs act as the dopamine D2 receptor blocker in the brain and discontinuance of the drug(s) is necessary for the treatment. Parkinsonian symptoms begin to improve in several weeks and patients are relieved from the symptoms usually within several months.