10 HCC cell lines and 122 surgically resected HCC were studied on chemosensitivity to 6 anticancer agents. Succinic dehydrogenase inhibition test was used for evaluating chemosensitivity of HCC. The HCC cell lines were positive in sensitivity to the most anticancer agents except 5-FU. Sensitivity of resected HCC specimens was positive in 17/42 (40.5%) to exposed to VP-16, in 21/57 (36.8%) to IFM, but also it was positive in 40/46 (87.0%) of the non-cancer tissue of the same liver exposed to VP-16 and in 33/60 (55.0%) to IFM. So VP-16 and IFM were probably considered to injure the residual liver after hepatectomy. In immunostainings of P-gp, GST-pi, MT, and P-450 of HCC cell lines, the expression of P-gp correlated with MDR1 mRNA and chemosensitivity test to ADM. Correlation between the expression of GST-pi and chemosensitivity test to ADM and CDDP were considered to be probably recognized. However, in surgically resected HCC, correlation among those factors was not observed.

Three cases of secondary acute myeloid leukemia (AML) that developed after long term treatment with oral etoposide were reported. Case 1 was a 72-year-old male in whom small cell lung cancer was diagnosed in January 1987. He developed AML (M4) in February 1993 after long-term treatment with oral etoposide (total dose 14,650 mg) t(9; 11) (p21; q23) with rearrangement of MLL genes was recognized. Case 2 was a 68-year-old female non-Hodgkin's lymphoma (NHL) was diagnosed in February 1989. AML (M4Eo) with inv(16) (p13q22) developed in March 1994 after long-term treatment with oral etoposide (total dose 5,100 mg). Case 3 was a 39-year-old male in whom NHL was diagnosed in January 1991. He developed AML(M2) with t(11; 19) (q23; p13) in May 1994 after long-term treatment with oral etoposide (total dose 20,450 mg). These three cases suggest that long-term treatment with oral etoposide may be associated with a risk of developing a secondary AML in patient with malignancies.

A late phase II study of LY188011 (gemcitabine hydrochloride), a new synthetic anticancer agent, was conducted at 20 Japanese institutions to evaluate the efficacy and safety of the agent administered alone in patients previously untreated with chemotherapy for primary non-small-cell lung cancer (NSCLC). All of the total 73 patients enrolled were eligible and 69 completed at least one course of LY188011 therapy. All patients were evaluated for safety. The response rate was 26.0% (19/73) of eligible patients. The most common adverse reactions included decreased hemoglobin, leukopenia, neutropenia, anorexia, nausea/vomiting, and malaise. Most adverse reactions were of grade 1 or 2 and only a few grade 3 or 4 reactions were reported. However, since a death occurred due to interstitial pneumonia, careful observation for this event is needed. Based on these results, it may be concluded that LY188011, a new anticancer agent, has adequate efficacy for the treatment of NSCLC and causes few clinically relevant adverse reactions.

An early phase II cooperative study of Gemcitabine Hydrochloride (abbreviated to "gemcitabine" herewith) was conducted in patients with a variety of solid tumors (i.e., lung cancer, gastric cancer, pancreatic cancer, colon/rectum cancer, cervical cancer, ovarian cancer and breast cancer) at 56 institutions. The aim of the first step (Step I) was to investigate the feasibility of gemcitabine in a variety of different solid tumors, including lung cancer regarding efficacy and safety. The aim of the second step (Step II) was as a result of step I (Responses were observed) to continue to investigate the efficacy and safety of gemcitabine in chemonaive patients with non-small cell lung cancer. As a Step I study, gemcitabine was administered once weekly at a dose of 800 mg/m2 for a consecutive 3-week period followed by a week of rest, in multiple courses. Among the 29 eligible patients with lung cancer, partial response (PR) was achieved in 3 patients (25.0%, 95% confidence interval: 5.5-57.2%) out of 12 chemonaive patients. Adverse reactions (grade 3 or higher) seen in 29 patients with lung cancer were neutropenia (27.6%), leukopenia (13.8%), decreased hemoglobin (13.8%), thrombocytopenia (10.3%), malaise (6.9%), anorexia (3.4%), nausea/vomiting (3.4%), diarrhea (3.4%), dyspnea (3.4%) and interstitial pneumonia (3.4%). In other types of solid tumors, PR was achieved in 2 (8.7%) out of 23 eligible patients with cervical cancer and in 1 (5.3%) of 19 eligible patients with ovarian cancer, while the use of analgesics became unnecessary in 1 patient with pancreatic cancer. Incidence as well as severity of main adverse reactions in these patients were comparable to those seen in patients with lung cancer. A Step II study, in which gemcitabine was administered once weekly at a dose of 1,000 mg/m2 to chemonaive patients with non-small cell lung cancer, was conducted, referring to the results of Step I and clinical studies conducted overseas. The results of the Step II study demonstrated PR in 5 (14.3%, 95% confidence interval: 4.8 - 30.3%) out of 35 eligible patients with non-small cell lung cancer and that the main adverse reactions were comparable to those seen in the Step I study, posing no tolerability problems in particular.

Phase I study on antimetabolic carcinostatic DMDC was conducted at 16 medical institutions nationwide for patients with various types of malignant tumors. DMDC was administered by intravenous infusion as per the following three schedules: single administration, single repeated administration, and 5-consecutive-day administration. The safety of the compound was examined single administration in 16 patients, by the single repeated administration in 5 patients, and by the 5 consecutive-day administration in 7 patients, for a total of 28 patients. In the single administration trial, 200 mg/m2 (1 n) was given as an initial dose, then increased stepwise to 450 mg/m2 (2.25 n). The single repeated administration trial was conducted at a single dose of 300 mg/m2. One treatment course lasts until recovery from side effects and abnormalities in laboratory test values. As a general rule, the administration was repeated for 2 treatment courses or more. In the 5-consecutive-day administration trial, an initial dose was 30 mg/m2/day (1 n), and increased to 40 mg/m2/day (1.3 n). The dose-limiting factors for both the single and 5-consecutive-day administration trials were decreases in the numbers of leukocytes and neutrophils. The maximum tolerated dose for single administration trial was over 400 mg/m2 (2 n), and for the 5-consecutive-day administration trial 40 mg/m2 (1.3 n). The decrease in the number of leukocytes and neutrophils for both the single administration and 5-consecutive-day administration trial reached its nadir one to two weeks after administration, and recovered in about one week. In the single repeated administration trial, the administration interval for patients who had completed 2 courses was 2 approximately 3 weeks. The plasma half-life of DMDC in the final phase of elimination in the single administration trial was 5.2 approximately 6.3 hours, and no differences were seen among dose levels. The urinary excretion rate was between 32.0 approximately 61.5% until 48 hours after administration. No accumulation was seen in the 5-consecutive-day administration trial. There were no findings to suggest an antitumor effect in the present study. Given the recovery pattern for suppression of marrow, the above mentioned results led us to decide that an recommended method of administration and dosage in an early phase II trial would be 300 mg/m2 per administration by an intravenous infusion every 2 approximately 3 weeks.

In order to investigate myocardial lipid metabolism in patients receiving chemotherapy regimens containing adriamycin (ADR) for hematological malignancies, 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT was performed. Thirty-two patients with hematological malignancies received a mean total ADR dose of 245 mg/m2 (range: 0-550 mg/m2). A polar map based on data from 8 normal individuals was used to calculate the extent score (representing the area of decreased uptake) and the severity score (representing the severity of defects) in the patients given ADR. 1) There was a significant association between the total ADR dose and the extent and severity scores. 2) The left ventricular ejection fraction was significantly associated with the extent and severity scores. 3) The two scores were also significantly associated with the washout rate of 123I-metaiodobenzylguanidine (MIBG). These results suggest that 123I-BMIPP myocardial scintigraphy reflects dysfunction of the myocardial mitochondria and serves as a guide for determining whether administration of ADR should be discontinued or the dose reduced.

We observed the effects of the retinoic acid (13-cis retinoic acid; 13-cis RA, and all-trans retinoic acid; ATRA) for the cell growth and the expression of CD 25 on peripheral blood mononuclear cells (PBMC) from 17 patients with adult T cell leukemia (ATL). Fourteen had acute type, 1 had chronic type, and 2 had smoldering type of ATL. We divided those patient into 3 groups (hyper-sensitive, sensitive and resistant group) by determined with reduction rate of [3H]-thymidine incorporation obtained before and after treatment with 13 -cis RA or ATRA respectively. Growth inhibition was not observed in normal PBMC by 13 -cis RA or ATRA. However, no down-regulation of CD 25 expression was observed on PBMC in all patients and normal individuals after treatment with 13-cis RA or ATRA. In the aspect of growth inhibition on PBMC in ATL patients, we tried to clarify the mechanism of the phenomenon. In agarose gel electrophoresis, extracted genomic DNA from retinoic acid treated PBMC in hyper-sensitive and sensitive ATL patients showed multimer DNA fragmentation pattern. On the other hand, genomic DNA from PBMC after treatment with retinoic acid in resistant ATL patients and normal individuals showed high molecular DNA pattern without fragmentation. Taken together, it is suggested that retinoic acid could induce growth inhibition of PBMC in some ATL patients resulting in DNA fragmentation, apoptosis. We deeply consider that retinoic acid may be an useful agent for ATL patients in clinical aspect.

The effects of epirubicin (EPIR), 5-fluorouracil (5-FU) and mitomycin C (MMC) on the vascular wall were examined histologically and pharmacologically. The popliteal arteries of rabbits were observed under a microscope one week after the injection of each anticancer drug. The histological change was not apparent. The rat thoracic aorta was removed and placed in the Krebs, solution. Helical strips were made, mounted in organ chambers and incubated with 10(5) mol/l (M) of each anticancer drug for 2 hours. After incubation, the relaxation response to acetylcholine (Ach) in endothelium-intact strips and that to sodium nitroprusside (SNP) in endothelium-denuded strips were evaluated. EPIR affected the relaxation response to Ach but not to SNP. 5-FU and MMC did not affect the relaxation responses to Ach and SNP. These results revealed that EPIR impairs the nitric oxide function at the level of endothelium. This effect of EPIR may be connected with arterial change following transarterial chemotherapy.

(-)-Epigallocatechin gallate (EGCG), the main constituent of green tea, inhibited a tumor promoting activity of okadaic acid in a two-stage carcinogenesis experiment on mouse skin. The group treated with a single application of 100 micrograms 7, 12-dimethylbenz (a) anthracene followed by repeated applications of 1 microgram okadaic acid resulted in 80% of tumor-bearing mice and 4.7 of average numbers of tumors per mouse in week 20. Repeated applications of 5 mg EGCG, prior to okadaic acid, completely inhibited the tumor formation in mice up to week 20. The inhibitory effects of EGCG with two different doses of each application, 1 mg and 5 mg, were dose-dependent. A topical application of 5 mg EGCG immediately reduced the specific binding of [3H]okadaic acid to a particulate fraction of mouse skin to as low as 30% of control. According to the Scatchard analysis, the reduction of specific [3H]okadaic acid binding was mainly due to the reduction of the binding sites, not due to the change of the affinity. The reduction of the specific binding was closely related to the inhibitory effct of EGCG on tumor promotion of okadaic acid. Since EGCG is a non-toxic compound, ingested in green tea in daily life in Japan, EGCG is one of the candidates for practical cancer chemopreventive agents.

A late phase II study of LY188011 (gemcitabine hydrochloride), a new nucleoside derivative, in patients with non-small-cell lung cancer (NSCLC) was conducted at 24 Japanese institutions shown in Table 1 with a total of 69 patients enrolled. Of these, 67 were eligible and 64 completed at least one course of LY188011 therapy. The response rates (partial response only) in these populations were 20.9% (14/ 67) and 21.9% (14/64), respectively. Serious adverse reactions were septic shock and interstitial pneumonia in one patient each. Grade 3 or 4 adverse reactions included neutropenia (22.7%), decreased hemoglobin (13.4%), leukopenia (10.4%), anorexia (10.4%), malaise (7.5%), and nausea/vomiting (6.0%). Based on these results, it may be concluded that LY188011 has a high efficacy and benefit for the treatment of NSCLC.

Effects of etoposide on the cell deaths of a human pancreatic cancer cell line by exposure to high-dose X-ray irradiation were examined. Both high dose X-ray irradiation and etoposide killed the pancreatic cancer cells by apoptosis. With 30 gray irradiation, simultaneous treatment of etoposide did not alter the percentage of cell deaths; however, 24-hr prior treatment of etoposide killed a significantly larger percentage of the cells, accompanying the accumulation to the S phase of the cell cycle. The results indicate that apoptosis of human pancreatic cancer cell line induced by high dose X-ray irradiation can be enhanced by prior treatment with etoposide.

The mechanism of the cause of hyperleukocytosis induced by differntiation induction therapy of acute promyelocytic leukemia (APL) by all-trans retinoic acid (ATRA) was studies. Of 11 patients treated by ATRA in our hospital, 3 developed hyperleukocytosis. Moreover, 2 out of 4 patients with retinoic acid syndrome (ATRA syndrome) had hyperleukocytosis. Using the patients' leukemia cells as test material, we obteined the following results. In the presence of ATRA at a concentration that induced differentiation in vitro, promotion or supression of differentiation and lineage determination during the differentiation of APL cells involved factors other than ATRA, such as cytokines. Moreover, APL cells that differentiated into monocytoid cells possessed the capability of producing endogenous cytokines such as TNF alpha, which might be involved in the development of ATRA syndrome. Compared to cells from patients without hyperleukocytosis they had a stronger TNF alpha producing capability and lower sensitivity to TGF beta, showing hyperdifferentiation in response to ATRA. Depending on the case, those with the same sensitivity to ATRA might show different sensitivities to cytokines.

In this review, I have attempted to provide an overview of the pathways by which cytotoxic drugs induce emesis. The mechanisms of serotonin 5-HT3 antagonists and new antiemetics are also discussed. Old data especially from the experiments employing area postrema ablation must be re-evaluated because it is likely that the operation has damaged other important nucleus in the brain stem. Therefore, the concept of the chemoreceptor trigger zone and "vomiting center" proposed by Borison et al. in 1950s is questionable. Nausea and vomiting caused by cytotoxic drugs have been a serious problem in anti-cancer therapy and prompted lots of scientists to find the mechanism and to develop antiemetics. Effectiveness of 5-HT3 antagonists were shown in late 1980s, and now they are clinically available. I have investigated their mechanisms using Suncus murinus and proposed that the pathways by which cisplatin, one of most emetogenic drugs, induces emesis are as follows: 1) cisplatin is converted to an active metabolite(s), 2) the metabolite(s) somehow produces oxygen free radicals in the enterochromaffin cells, 3) the free radicals release serotonin, 4) the released serotonin stimulates 5-HT3 receptors located on the vagus afferents, 5) impulses are transmitted to the brain stem, or emetic pattern generator and initiate emetic reflex. Therefore, scavengers of free radicals and antioxidants can be a new type of antiemetic drug.

Seventeen patients with advanced breast cancer were treated with neoadjuvant intraarterial chemotherapy with high dose epirubicin. The following results were obtained. 1. Excellent down-staging effect (tumor reduction > 50% of its original size: 82.4%) was confirmed on primary lesions. In addition, an objective response rate of 37.5% was observed at the metastatic sites. 2. Leukopenia, which was the dose-limiting factor in this regimen, appeared at the frequency of 82.4%. Therefore, we needed G-CSF and/or a sufficient interval between each cycle. 3. A great number of cases and sufficient follow-up period will be indispensable to discuss survival in future investigation.