Glutathione (gamma-Glutamylcysteinyl glycine, GSH) exists in almost all cells in a millimolar order of concentration. GSH plays an important role in protecting cells against oxidative stress, maintaining a reducing environment within the cells, and inactivating many xenobiotics. Synthesis of GSH is regulated by gamma-glutamylcysteine synthetase (gamma-GCS). Increase in the activity of gamma-GCS has been found in many drug-resistant cancer cells. It is believed that GSH plays a role in the aquisition of resistance to anti-cancer drugs, such as a cisplatin, adriamycin, melphalan, or taxol. In this paper, the possible mechanism of GSH involvement in drug-resistance and new approach for the depletion of GSH by suppressing the expression of gamma-GCS are introduced.

Antimitotic agents are expected to exert the high antitumor potency on various solid tumors. One of the determining factors for the sensitivity/resistance to these antimitotic agents is the status of the tubulin to which these drugs bind. Quantitative and qualitative changes such as gene mutations of the beta-tubulin were suspected to be major determining factors. Microtubule-associated proteins and the related signaling by the mitogen-activated protein kinase cascade are also considered to be factors influencing the sensitivity/resistance of the tumor cells to the antimitotic agents. These are promising targets for development of new antimitotic agents.

Recent studies on angiogenesis in human solid tumors have underlined its importance as therapeutic target. In particular, of interest is to suppress the function of several positive regulators including vascular endothelial growth factors (VEGF), basic fibroblast growth factor and thymidine phosphorylase, because they are evident to be responsible for the promotion of neovascularization in a variety of tumor types. In this review, we picked up VEGF, probably one of most promising target, and discuss about the therapeutic tools for controlling VEGF function in human tumors.

Numbers of molecular targets for anticancer agents have been increased during the recent scientific progress in cancer biology. Of these targets, one should understand which target is clinically applicable. The forthcoming approach to evaluate such "molecular targets" is expected to provide novel diagnostic markers for adequate cancer therapy, and also novel targets for development of potent and useful therapeutic agents.

In 1993 eighteen Japanese patients with cancer and herpes zoster, a viral disease, died from interactions of the new oral antiviral drug, sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), with oral anticancer prodrugs of 5-fluorouracil (5-FU) within 40 d after SRV was approved by the Japanese government and began to be used clinically. Before the death, most of these patients had severe symptoms of toxicity, including diarrhea with bloody flux and marked decreases in white blood cell and platelet counts. All of these patients received SRV daily for several days while being administered long-term anticancer chemotherapy with one of the oral 5-FU prodrugs. There was no acute toxic symptom in patients who received SRV alone or SRV and the other types of anticancer drugs. A toxicokinetic study was carried out using rats to investigate the mechanism of the acute death in the patients caused by drug interactions between SRV and 5-FU prodrugs. Rats were orally coadministered SRV with tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil), a 5-FU prodrug that most of the patients were considered to receive before the death. All the rats receiving SRV and FT once daily showed extremely elevated levels of 5-FU in the plasma and tissues, including bone marrow and small intestines, and died within 10 d, while the animals given the same repeated dose of SRV or FT alone were still alive over 20 d without any appreciable toxic symptom. Before their death, there were a marked damage of bone marrow, a marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported for the patients. Data obtained by in vivo and in vitro studies indicated that (E)-5-(2-bromovinyl)uracil (BVU), generated from SRV by the gut flora and absorbed through the intestinal membrane, was reduced in the presence of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme regulating the tissue 5-FU levels from FT, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU. An irreversible inactivation by BVU of rat and human DPDs, expressed in E. coli for the latter, was observed in the presence of NADPH with their purified preparations in a manner reciprocal to radiolabelling of the enzyme proteins with [14C]BVU. SRV showed no inhibitory effect on the rat and human DPDs in the presence of NADPH.

Acute respiratory failure (ARF) occurred at the time of leukocyte recovery promoted by granulocyte colony-stimulating factor (G-CSF) in three patients with the preceding infection (S. aureus pneumonia, varicella zoster, and P. aeruginosa bacteremia, respectively) which had developed during leukopenia after cancer chemotherapy. G-CSF was used for 4 to 6 days, and the leukocyte counts at onset of ARF were 19,300/microliter, 11,300/microliter, and 4,100/microliter, respectively. All of the three patients received high-dose methylprednisolone and the artificial respiration was used in two. Consequently two patients responded well and survived, but one died of respiratory failure 2 weeks after occurrence of ARF. Autopsy of the dead case revealed mild interstitial pneumonia in the both lungs together with bacterial pneumonia in the right lobe. These cases indicate that G-CSF-induced leukocyte recovery can cause severe ARF in patients with precending infection. Therefore, G-CSF should be administered very carefully to granulocytopenic patients with infection.

For a sample of 136 adults on whom Doxorubicin (DXR) had been used, we looked for the ejection fraction (EF) by echocardiography and examined its relationship with the amount of DXR. Our results showed that as the amount of DXR increased the EF decreased significantly, particularly with aging. The use of previous mediastinal radiation and 5-FU, etc. on breast cancer patients had no effect on the EF. From our examination of patients developing congestive heart failure, we repeatedly performed echocardiography and found that DXR can be safely used until the EF decreases to 55 percent. In this way, we can find many patients with whom it is possible to use DXR in larger amounts than 550 mg/m2. In general, large quantities of DXR can be used on young people, but for elderly people, large quantities of DXR should be used with caution.

The Japan Society for Cancer Therapy Committee of Criteria for Efficacy of Cancer Therapy proposed new toxicity grading criteria called "Adverse Drug Reaction Criteria". The basic principles of the JCOG Toxicity Criteria were applied to the Adverse Drug Reaction Criteria of the Japan Society for Cancer Therapy with the following modifications: 1. In Grade 4 toxicity for stomatitis, "requires preventative intubation" was changed to "requires enteral support". 2. In Grade 0 for proteinuria, "none" was changed to "no change". (in addition, the definitions of Grade 1 to 3 toxicity for proteinuria were changed to concentration of proteinuria adapted to Japanese.) 3. The toxicity grading criteria was named Adverse Drug Reaction Criteria of the Japan Society for Cancer Therapy.

Pulmonary disease induced by chemotherapeutic drug or radiation is one of the major cause, of death in patients with lung cancer. Many of these patients die from interstitial lung disease despite discontinuation of the drug and addition of corticosteroid treatment. The clinical presentation is similar for all of the chemotherapeutic drugs. For the early detection of interstitial lung disease due to a chemotherapeutic drug, serial measurements of the CO diffusing capacity (DLco), serum LDH, and serum KL-6 are useful. The first step in treatment is withdrawal of the drugs, and pulse therapy by using methylprednisolone is used as a standard therapy for interstitial lung disease due to chemotherapeutic agents. Immunosuppressive agents, such as cyclophosphamide or azathioprine, might be used as second-line drugs in patients for whom drugs either failed or could not tolerate corticosteroid treatment. Thus the usefulness of this therapy is unknown, and it should be considered as a marginal therapy. To develop an investigational therapy for the chemotherapeutic drug-induced interstitial lung disease, we investigated the efficacy of a new specific neutrophil elastase inhibitor (ONO-5046.Na) in bleomycin-induced pulmonary fibrosis. The inhibitory effect of ONO-5046.Na was observed in bleomycin-induced pulmonary fibrosis in mice. This specific neutrophil elastase could be a investigational therapeutic agent for interstitial lung disease due to chemotherapeutic agents used against lung cancer.

Using a reverse transcriptase-polymerase chain reaction (RT-PCR)-based quantitative analysis method, we investigated MDR1 mRNA expression levels in 58 bladder cancer specimens to determine whether MDR1 gene expression was induced or enhanced in bladder cancers during chemotherapy. In bladder cancer specimens which were obtained from patients treated with anticancer drugs, significantly higher expression levels of MDR1 mRNA were observed than in those from patients not treated with any anticancer drugs (p = 0.0134, Mann-Whitney U test). From 14 patients who had bladder cancer, clinical specimens were obtained before and after neoadjuvant intra-arterial chemotherapy. The expression levels of MDR1 mRNA were significantly higher in the post-treatment specimens than in the pre-treatment specimens (p = 0.0298, Wilcoxon signed-rank test). Of these 14 patients, 7 patients exhibited increased levels of MDR1 mRNA expression after chemotherapy. In 6 patients, there were no changes in the MDR1 mRNA expression levels before and after chemotherapy. Only one patient exhibited decreased levels of MDR1 mRNA expression after chemotherapy. No significant correlations were observed, between MDR1 mRNA expression levels and effect of the chemotherapy determined microscopically, dosage of anticancer drugs, or patient outcome. In conclusion, this study indicates that MDR1 gene expression in bladder cancers is induced and enhanced during chemotherapy. This overexpression of the MDR1 gene may contribute to resistance to anticancer drugs after repeated chemotherapy.

A 26-year-old woman was admitted to our hospital for lumbago on November 29, 1995. The white blood cell count was 6,500/microliter with 26.5% myeloblasts and the bone marrow was hyperplastic due to myeloblasts. Myeloblasts were negative for myeloperoxidase and positive for alpha-naphthyl butylate esterase, CD11a (89%), CD11b (38%), CD11c (92%), CD33 (91%) and HLA-DR (58%). Chromosomal abnormalities were recognized: 46, XX, t(9;11) (p22;q23), 45, XX, -7, t(9;11) (p22;q23) and 47, XX, +19, t(9;11) (p22;q23). Acute myeloblastic leukemia (M5a) was diagnosed. Disseminated intravascular coagulation was also present. The patient received induction therapy and achieved remission on January 9, 1996, but myeloblasts increased to 3.6% in bone marrow despite consolidation therapy. Low doses of cytarabine (AraC) and etoposide were instituted on March 7, granulocyte colony-stimulating factor (G-CSF) was started on March 15, and pronounced skin infiltration developed on March 18. The patient received reinduction therapy from April 16 and administration of G-CSF was combined for 2 days, and a marked increment of myeloblasts in the peripheral blood was observed. After discontinuation of G-CSF, myeloblasts decreased and skin infiltration disappeared. However, the patient died of cerebral infiltration on June 30. The response of myeloblasts to G-CSF by in vitro liquid culture was noteworthy. The present case stresses the requirement for great caution to be exercised in the use of G-CSF in patients receiving low dose AraC.

The effect of the anthracycline analogue, pirarubicin, on cardiac function was examined. One hundred and four patients with gynecologic malignancies were treated with 40-50 mg/body THP ADM every 3 to 4 weeks by iv bolus injection. Three out of 104 cases that had developed cardiac failure received more than 1,500 mg. One case receiving 1,340 mg developed cardiac failure and expired 3 years after completion of treatment for malignancy. From the above experience, it is concluded that the MTD of pirarubicin seems to be 1,500 mg/body or 1,100 mg/m2.

PyNPase activity, MMPs activity and serum IAP values were measured in tumor tissues from colorectal cancer patients who had been divided into two groups, one given preoperative 5'-DFUR and the controls. PyNPase activity of the preoperative administration group was approximately equivalent to that of the controls. In the control group, correlations were assessed between PyNPase activity and activities of MMP1 and MMP3. To assess the effect of 5'-DFUR on the activity of MMPs, we divided patients into two groups, a high and a low PyNPase activity group. Although there was no correlation with MMPs activity of the preoperative administration group and the control group in the low PyNPase activity group, the activities of MMP1 and MMP9 of the control group were significantly higher in the high PyNPase activity group. Moreover, the serum IAP value of the administration group was significantly lower than that of the control group. These results indicated that PyNPase activity was thus suggested to be somehow related to MMPs activity and serum IAP values.

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.

Pharmacokinetic parameters after intra-peritoneal administration of cis-platinum (CDDP) were evaluated and compared with those after intravenous administration. CDDP at a dose of 70 mg/m2 were administered intra-peritoneally in 5 patients with advanced gastric cancer (IP group). Pharmacokinetic parameters and toxicities were evaluated in these patients and compared with those in 4 esophageal cancer patients administered the same dose of CDDP intravenously (IV group). In IP group, Cmax of total- and free-Pt were 3.41 +/- 0.89 micrograms/ml and 1.10 +/- 0.30 micrograms/ml, and AUC of total- and free-Pt were 59.6 +/- 14.3 micrograms.hr/ml, 3.12 +/- 0.89 micrograms.hr/ml, respectively. On the other hand, Cmax and AUC of total- and free-Pt in IV group were 3.31 +/- 0.59 micrograms/ml. 1.13 +/- 0.21 micrograms/ml and 45.89 +/- 9.24 micrograms.hr/ml, 1.22 +/- 0.8 micrograms.hr/ml, respectively. AUC of free-Pt in IP group was significantly higher than in IV group. This result suggests that a more promising antitumor effect will be obtained systemically by intraperitoneal administration of CDDP. The incidence and grade of toxicities were similar in these two groups.

Arterial infusion chemotherapy is considered to be an extremely effective treatment for liver metastasis from colorectal cancer in terms of its tumor reduction and preventing recurrence in residual liver after resection. However, there still remain some unclear points as to the influence on hepatic artery and bile duct when this treatment is used over the long term. We report some conclusions obtained by examining cases of hepatic arterial occlusion (stenosis) and biliary complication who received this treatment.

Fourteen patients with unresectable primary or metastatic liver cancer were divided into two groups: group A, continuous hepatic arterial infusion of 5-FU in 10 cases; group V, continuous intravenous infusion of 5-FU in 4 cases. In group A, 5-FU (360 mg/m2/day x 5 days/week x 4 weeks) was continuously infused into the hepatic artery via femoral or gastroduodenal artery through Infuse A Port. In group V, 5-FU (360 mg/m2/day x 2 weeks) was continuously infused into the subclavian vein through IVH route. On day 1, the concentration of 5-FU in peripheral blood in group A (12.1 +/- 12.8 ng/ml) was significantly lower than in group V (43.8 +/- 19.8 ng/ml, p = 0.004). On day 5, it was also decreased in group A (24.6 +/- 24.1 ng/ml) compared with that in group V (61.8 +/- 34.4 ng/ml, p = 0.039). Side effects of 5-FU like nausea, abdominal discomfort and stomatitis were recognized in 4 out of 10 patients in group A (40%) and 3 out of 4 patients in group V (75%). In group A, a complete response was obtained in one patient with synchronous multiple liver metastases of sigmoid colon cancer. These results suggest that systemic toxicity of 5-FU is alleviated by continuous hepatic arterial infusion in the patients with unresectable liver cancer because of its low concentration in peripheral blood.

The causes of extra-arterial dislocation of indwelling catheter (EAD), which was one of the serious complications in arterial infusion chemotherapy, were examined. Subjects were six cases of EAD among the 45 cases of gastric cancer with liver metastases treated with hepatic arterial infusion chemotherapy. According to the route of cannulation, EAD occurred more frequently in the cases of cannulation via gastroduodenal artery (18.5%) than in those via subclavian artery (5.5%). Concerning the drugs and their administration, all cases of EAD were treated by continuous injection of 5-fluorouracil (5-FU). Main symptoms of EAD were high fever, abdominal pain and anemia, which developed after administration of total doses from 4.0 g to 30.5 g of 5-FU. In conclusion, it was strongly suggested that arterial destruction due to the toxicity of 5-FU caused EAD in hepatic arterial infusion chemotherapy, especially in cases of cannulation via gastroduodenal artery due to the high concentration of 5-FU in a limited part of the arterial wall.

A 48-year-old man underwent left hemicolectomy and right extended hepatectomy for colon cancer and its synchronous multiple liver metastasis. Sixteen months after, multiple metastases in the remnant liver were found, so he was given bolus hepatic infusion of 5-FU 1,000 mg/week, total amount, 25 g. The response was CR, but he developed a liver abscess in segment 4.