The regional toxicity of an anticancer agent for normal liver tissue following hepatic arterial infusion chemotherapy (HAI) was evaluated in terms of morphology, function, and histopathology. Forty-two patients(M:F = 30:12; mean age, 59.9 years) with liver metastases from colorectal cancer were treated with HAI using a totally implantable vascular access port system from July 1994 to March 1999. The regimen used here was so-called weekly high-dose 5-fluorouracil(5-FU) infusion(5-FU, 1,000 mg/m2/week). Volume measurement of the liver demonstrated not only whole liver atrophy including the tumor but also volume reduction of the non-tumorous lobe. Atrophic change of the liver was seen in patients who were administered over 20 g/m2 of 5-FU(p < 0.01). The CT attenuation values of the liver were examined, and fatty infiltration was seen in six patients. Histologic examination of liver biopsies from the non-tumorous part revealed steatosis and infiltration of inflammatory cells in the portal triad, which were not seen in specimens prior to HAI. On clinical laboratory findings, enzymes representing bile duct, including alkaline phosphatase, leucine amino peptidase, and gamma-glutamyltranspeptidase, were increased in 22 patients. In terms of regional toxicity for long-term HAI, 20 g/m2 of 5-FU, is the key dose at which to consider temporary cessation or dose reduction.

We describe herein two newly diagnosed patients with acute myelogenous leukemia (AML), who were treated twice with an idarubicin hydrochloride (IDR)-containing regimen as a response-orientated induction therapy. Both patients had severe gastrointestinal tract hemorrhage complications at their nadir. The two patients were as follows: a 35-year-old male, FAB-M4, and a 47-year-old female, FAB-M0. They received the same induction chemotherapy (IDR 12 mg/m2 for four days and cytarabine 100 mg/m2 for ten days). No response (NR) was obtained in either, so they underwent the same regimen again. During the period of myelosuppression, they developed severe gastrointestinal hemorrhage. One died of sepsis, and the other of acute respiratory distress syndrome without a recovery in bone marrow. The fetal gastrointestinal tract complications may have been due to severe myelosuppression and mucosal damage in these patients. Careful observation will be needed to prevent such severe complications after the treatment with IDR.

A 17-year-old boy suffered from osteosarcoma in his left distal femur. He was treated with 4 courses of HD-MTX preoperatively, then a wide resection and replacement with endprosthesis was performed. After surgery, 4 more courses of HD-MTX were administered. In the last course of HD-MTX, the serum level of MTX had not decreased to a safe level after 48 hours following MTX administration. Liver and renal dysfunction then occurred, so massive leucovorin rescue and hemoperfusion were done. Fortunately, all complications disappeared. The patient is alive and well, and has been disease free for six years since surgery.

The incidence of nausea and vomiting or anorexia was investigated in 16 outpatients receiving oral antimetabolites such as 5-FU (fluorouracil) as chemotherapy, during a maximum observation period of 28 days. In those patients who experienced the above symptoms which meet the standard defined in the study protocol, ondansetron hydrochloride tablets in a 4 mg/day dose were given based on the decision of the physician in charge, and its efficacy in those patients was examined. Nausea and emesis or anorexia was observed in six cases (37.5%) during the period of observation. Anorexia appeared in a majority of the above cases, with an incidence rate was 31.3% (5/16 cases). In two of the cases, anorexia improved after ondansetron tablets were administered. No adverse drug reaction was reported with ondansetron tablets. We conclude that although antimetabolites have low emetogenicity, as anorexia appeared in approximately 30% of the patients, the use of ondansetron tablets or other antiemetics should be considered in order to maintain patients' QOL and drug compliance.

We investigated the chemosensitivity of anticancer agents against primary (230 patients, 268 tumors) and recurrent breast cancer (40 patients, 51 tumors) using histoculture drug response assays (HDRA) of surgical specimens. Of the 40 recurrent breast cancer patients, 26 were pretreated with anthracycline. The efficacy of the agents was assessed according to an inhibition index of optical density detected by an ELISA reader. The inhibition rate of docetaxel against recurrent tumors was similar that against primary ones, although the rates of adriamycin, 5 fluorouracil, mitomycin and cisplatin against recurrent tumors were significantly lower than those against primary ones. The clinical response of docetaxel was also evaluated in ten patients with recurrent breast cancer. Of the ten patients with recurrent breast cancer, eight were pretreated with anthracycline, and seven showed a partial response. These results indicate that docetaxel is effective against recurrent breast cancer, even anthracycline-resistant breast cancer.

To investigate whether chlormadinone acetate (CMA) could prevent the flare-up phenomenon induced by a luteinizing hormone-releasing hormone analogue (LH-RHa), we treated 4 cases of stage C and 17 cases of stage D prostate cancer with CMA for 4 weeks and CMA plus monthly injection of LH-RHa for following 24 weeks. Serum LH, testosterone, and prostate-specific antigen (PSA) levels were closely monitored before and 3 days, 1-, 2-, and 4-weeks after LH-RHa injection. Subjective and objective responses were also investigated. Serum LH and testosterone levels significantly elevated 3 days after the initial injection of LH-RHa. However, they resumed 1 week after LH-RHa injection with fluctuation under the normal range. Out of 21 cases, 3 cases (14%) consisting of 2 poorly and 1 moderately differentiated adenocarcinoma showed increased serum PSA levels 1 week after LH-RHa injection in spite of suppressed serum testosterone levels. The objective response of these 2 poorly differentiated cases was progressive disease at 24 weeks. No cases indicated worsening of clinical symptoms concerning flare-up phenomenon. CMA seemed to be capable of preventing flare-up phenomenon in advanced prostate cancer.

This paper is a review of three topics related to bio-trace metals. First, the transfer of metals into tissues of patients with chronic diseases treated with hemodialysis is examined. Such diseases include chronic hepatitis, diabetes, and chronic renal failure. In these diseases, metal contents from fingernails were flexible but non-specific. Toxicity may appear as the amount of heavy metals in tissues of patients with chronic renal failure treated with hemodialysis. For example, cadmium and lead were not excreted from the blood of patients during the hemodialysis treatment, and, therefore, their amounts gradually increased in the blood of patients. The level of zinc increased and was excreted in the urine of diabetic patients and experimental animals. Calcium accumulated in the kidney of streptozotocin (STZ)-induced diabetic rats that were fed low zinc diets; and, as a result, severe renal failure occurred. From these results, complication syndromes of either metal deficiency or excesses may occur in tissues of patients with chronic diseases. Second, the role of metallothionein (MT), an inducible protein, and the properties of MT isoforms have been studied on experimental animals. In the exocrine cells of the pancreas, MT was induced by various stresses such as zinc, STZ, alloxan and 4-aminopyrazolo-(3,4-d) pyrimidine, but the effects of those stresses were not clear in the endocrine cells. Therefore, MT may have a role in the exocrine cells of the pancreas. In addition, we were able to separate completely MT-1 and MT-2 isoforms in cytosol fractions of tissues using a capillary zone electrophoresis system at neutral pH without any detergents. Each role of the MT isoforms in the tissues soon started to become clear. Third, cisplatin, a platinum-containing anti-tumor drug, did not penetrate into the brain tissue under physiological conditions, as there is a blood-brain barrier to cerebral tissues; however, it did penetrate with either short-term hypoxia or in the case of lipopolysaccharide-treated experimental animals. Nitric oxide, prostaglandin, and free radicals are related to the penetration. Older rats had a higher sensitivity to cisplatin than younger rats.

In general, the root of a seaweed is poorly developed as compared with its thallus and is called the rhizoid or holdfast. In Laminaria, belonging to Phaeophyceae, although the thallus is used for food, the rhizoid is considered an unuseful natural resource. We attempted to detect anti-breast cancer substances from that resource. As a result, a substance having a weak absorptivity to aluminium oxide and Sephadex G-25 was found. According to analysis of the FAB-MS spectra and 1H NMR spectra, the substance was identified as tryptophan, an amino acid. Finally, it was concluded by a chiral column-HPLC method that the tryptophan was the L-form.

We report 3 cases of suicide attempts in postoperative patients with renal cancer after alpha interferon withdrawal. In the first patient, depression occurred during interferon therapy, and remained after interferon withdrawal. A suicide attempt occurred 7 months after interferon withdrawal. In the second and third patients, depression did not occur during interferon therapy, but suicide attempts occurred 40 days and 7 months after interferon withdrawal, respectively. Depression does not always disappear after interferon is discontinued. Psychiatric supervision should be continued even more frequently after interferon withdrawal. The increased risk of psychiatric side effects due to interferon, as well as their severity, suggest that interferon should be administered with caution.

We report a case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after the patient had received several anti-cancer drugs, including vincristine (VCR), in a patient with myeloid antigen positive acute lymphoblastic leukemia (My(+)-ALL). A 53-year-old woman presented at the hospital complaining of high-grade fever and general lassitude. Further examination revealed that she had My(+)-ALL. On admission, she was treated with anti-cancer drugs, including VCR. On day 24, after the first administration of VCR, a conscious disturbance suddenly occurred and she was diagnosed with SIADH. A plain head CT scan showed a low density lesion through the gray matter to the white matter in the bilateral occipital lobe, as well as diffuse swelling of the cerebrum. This was not seen on the follow up CT scan, and we concluded that it had been a transient abnormal finding due to SIADH. She achieved complete remission after induction chemotherapy and 3 added courses of consolidation chemotherapy. VCR was also administered 4 times in the second consolidation chemotherapy, but hyponatremia did not occur. This case suggests that a head CT scan is a useful procedure for the diagnosis and monitoring of SIADH, and that VCR may still be used in a patient who has suffered from VCR-induced SIADH.

A multicenter co-operative late phase II study of raltitrexed (ZD1694), a specific thymidylate synthase (TS) inhibitor, was conducted in chemotherapy-naive patients with advanced colorectal cancer. Raltitrexed was infused intravenously over 15 minutes once every three weeks. Between April 1996 and September 1998, 61 patients were enrolled and 58 were eligible. Fourteen patients experienced a partial response (PR), 22 no change (NC), 20 progressive disease (PD) and 2 no evaluable (NE). The overall response rate was 24.1% (95% CI: 13.9-37.2%). Responses were seen in lung (22.7%), liver (22.9%) and deep lymph nodes (10.0%). Median survival was 11.6 months. Grade 3 or 4 toxicities were: leukopenia (13.8%), neutropenia (24.1%), hemoglobin decrease (15.5%), FBC decrease (6.9%), hematocrit decrease (6.9%), thrombocytopenia (6.9%), transient SGPT increase (6.9%), nausea/vomiting (20.7%), anorexia (15.5%), and asthenia (6.9%). These adverse reactions were considered to be manageable. Only one death was associated with drug treatment. These results suggest that raltitrexed provides an effective and convenient treatment for patients with advanced and previously untreated colorectal cancer.

Severe hepatotoxicity occurred in a prostate cancer patient treated with 375 mg of flutamide per day, 125 mg three times a day, for 11 weeks. Serial measurements of serum concentrations of flutamide and its metabolites in the patient showed an unusually high serum level and delayed elimination of flutamide and suggested decreased metabolic activity of oxidation of flutamide to OH-flutamide. In 37 patients with prostate cancer we periodically monitored the serum concentrations of flutamide as well as liver function parameters. In 2 patients, glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) elevated over 100 IU/L, and treatment with flutamide was discontinued. Slight elevation of GOT and GPT over 40 to 100 IU/L was also detected in 5 patients, and flutamide was withdrawn. The elevated GOT and GPT in these 7 patients recovered to the pretreatment levels after discontinuation of the treatment. In these patients with flutamide-induced hepatic disorders, the average serum concentration of flutamide was higher (2.76 times, and that of OH-flutamide was lower (0.76 times), as compared with patients who maintained normal liver function.

We encountered a 65-year-old woman with diffuse large B-cell lymphoma showing t(8;14)(q24;q32) and c-myc gene rearrangement that developed following 12 years of melphalan-based chemotherapy for multiple myeloma. Short-term remission was obtained by CHOP chemotherapy. However, shortly thereafter the patient died of an aggressive progression of lymphoma. It was suspected that the lymphoma was a secondary malignancy related to the treatment with cytotoxic agents and radiation for prolonged multiple myeloma. The chromosomal abnormality t(8;14)(q24;q32) is rare in secondary malignancies. Overexpression of c-myc by gene rearrangement may be associated with clinical courses manifested by the rapid progression of lymphoma.

We conducted a multicenter phase II clinical study of fludarabine phosphate, a new purine nucleotide analogue, in patients with chronic lymphocytic leukemia (CLL). Fludarabine phosphate was administered at a dose of 20 mg/m2/day intravenously for 5 days every 4 weeks as one course. Six courses as a maximum were repeated. The response rate was 38.5% (95% confidence intervals: 20.2% to 59.4%), with 1 complete remission and 9 partial remissions out of 26 treated patients. Major drug-related adverse reactions were fever, nausea, weakness, and paresthesia of the fingers; as a grade-3 reaction, varicella was also reported. Neutropenia and thrombocytopenia were observed as manifestations of hematologic toxicity. Clinical laboratory test results revealed abnormalities in hepatic function, including increased GPT, but none of these was rated grade 3 or 4.

The authors studied the hemodynamics of 5-FU hepatoarterial infusion in a colorectal cancer patient with multiple liver metastases, who had chronic renal failure maintained by hemodialysis. Under weekly high dose 5-FU hepatoarterial infusion (1,000 mg/m2, 5 hours), on a non-dialysis day, serum 5-FU concentration was 1,090 ng/ml just after the 5 h infusion, 391 ng/ml at 15 min, 217 ng/ml at 30 min, 47 ng/ml at 60 min, and < 4 ng/ml at 120 min after infusion. On a dialysis day it was 1,500 ng/ml just after infusion, 41 ng/ml at 15 min, 5 ng/ml at 30 min, and < 4 ng/ml at 60 and 120 min after infusion. A control group (n = 4), who had liver metastases from colorectal cancers and normal renal functions, showed 5-FU serum concentration of 987 +/- 384 ng/ml just after infusion, 226 +/- 117 ng/ml at 15 min, 18.5 +/- 5.8 ng/ml at 30 min, < 4 ng/ml at 60 and 120 min after infusion. The serum 5-FU concentration of the patient was maintained higher on non-dialysis days, while it decreased more rapidly on dialysis days than that of the control group. There were no clinical complications due to the weekly high dose 5-FU hepatoarterial infusion. Under the treatment of continuous 5-FU hepatoarterial infusion (500 mg/day), the serum 5-FU concentration of this patient was kept under 115 ng/ml. After hemodialysis, the concentration decreased. The serum 5-FU concentration of the control group (n = 4) was under 66 ng/ml. There were no side effects under the protocol of continuous 5-FU hepatoarterial infusion. 5-FU hepatoarterial infusion for liver metastasis was a safe treatment for a renal failure patient with hemodialysis.

The photosensitizing dye merocyanine 540 (MC540) has been used in preclinical models and in a phase I clinical trial in the U.S.A. for the extracorporeal purging of autologous bone marrow grafts contaminated with leukemia or lymphoma. In this communication, we report MC540-mediated photodynamic therapy (PDT) was effective in purging leukemic cells expressing P-gp. When K562 and K562/ADM were exposed to MC540 (15 micrograms/ml) and white light (145.8 kJ/m2), the concentration of K562 and K 562/ADR was reduced by 1.8 and 3.0 log, respectively. Using flow cytometry and confocal laser scan microscopy, MC540 and calcein-AM were bound intracellularly and effluxed by P-gp in K562/ADM. In K562/ADM, calcein-AM efflux was inhibited by P-gp modulator, cyclosporin A (5 microM) and verapamil (15 micrograms/ml). In contrast, MC540 efflux was inhibited by cyclosporin A but not verapamil. Furthermore, MC540-mediated PDT inhibited efflux of calcein-AM and MC540, and induced the accumulation of dyes in K562/ADM. We conclude that MC540 is a substrate of P-gp and that MC540-mediated PDT is useful for purging MDR cells through inhibition of P-gp activity.

The relationship of 5-FU-sensitivity to thymidylate synthase (TS) was investigated in a total of 82 gastric cancers of stage III or IV. The sensitivity test was done by Histoculture Drug Response Assay and TS expression was stained immunohistochemically using anti-TS antibody. Sensitivity to 5-FU of more than 50% of the inhibitory index (high sensitivity) was observed in 28.1% of the materials, less than 50% (low sensitivity) in 71.9% and less than 20% in 50.0%. The expression of TS was found in 25.6% of the patients. The incidence of positive TS expression was 34.5% in the high sensitivity group, against 22.0% in the low sensitivity group, with no statistical difference between them. No particular relationship was found between 5-FU-sensitivity group and TS expression rate when the tumor-histology was divided into high and low differentiation. In the present study, the ratio of patients negative for TS among the high 5-FU-sensitivity group both was 65.2%, both of which have been reported as producing high survival rates. In contrast, the ratio of patients positive for TS in the low 5-FU-sensitivity group was 22.0%. From these results, TS is considered to be responsible for approximately 40-50% of either high or low 5-FU-sensitivity, respectively, when the lower TS expression in the present study was taken into consideration and corrected.