An experimental model for hepatic metastasis with a transplantation route of free-pedicled subcutaneous-embedded spleen was established in BALB/c mice. Colon-26 tumor cells to produce hepatic metastasis were inoculated into the spleen and the influence of surgical stress by means of a 20-min exposure of the abdominal cavity on the incidence of hepatic metastasis was examined. Hepatic metastasis was more promoted by the surgical stress in order when it was given on the same day, the 7th day and the 3rd day of the inoculation. Administration, without surgical stress, of ASGM 1, a specific inhibitor of the natural killer activity, also facilitated the hepatic disease. Administration of OK-432 prior to the surgical stress or ASGM 1 was at least partly effective for prevention of the hepatic metastasis and prolonged the survival of the inoculated mice. Preoperative immunotherapy utilizing OK-432 might be a possible means to prevent hepatic metastasis triggered in colorectal surgery for cancer.

MX2, a new lipophilic morpholino anthracycline, has been reported to have superior chemotherapeutic effects to adriamycin against murine and human tumor cells. In this study the chemotherapeutic effect of MX2 against C6 glioma cells was examined as well as the photocytotoxicity of MX2 and the combination effect of MX2 and photodynamic therapy (PDT) in vitro. Colony formation is inhibited even with only 2 hour treatment with MX2 in a dose-dependent manner. In this colony forming efficiency assay the drug concentration required for 50% inhibition of colony formation for C6 glioma cells was 24.0 +/- 4.5 ng/ml. Mild photocytotoxicity of MX2 against C6 glioma cells was observed at a high concentration (100 ng/ml) of MX2 following exposure to white light but not red light. In combination, MX2 and the photosensitizer haematoporphyrin derivative (HpD) exhibited an additive cytotoxic effect against C6 glioma cells when the cells were treated with MX2 either immediately after red light illumination following incubation with HpD or at an interval of 24 hours before incubation with HpD. We conclude that MX2 may be clinically useful against malignant glioma alone, and in combination with other therapies such as PDT.

Effects of 40 micrograms/kg of granisetron monotherapy (K group) and concurrent therapy with a steroid (KS group) on acute and delayed emesis induced by cancer chemotherapy which included CDDP at a dose of 60 mg/m2 or more were compared in random clinical trials under the central registration method. In KS group, either 500 mg of methylprednisolone succinate or 8 mg of dexamethasone phosphate was given prior to granisetron administration. Clinical symptoms such as vomiting, nausea and anorexia were better in KS group than in K group, on any day from day 1 to day 7, and there was a statistically significant difference on day 1 and day 2. The cumulative total control rate throughout the period of seven days was also significantly higher in KS group. KS group was rated higher in the final clinical evaluation based on doctor's impressions, but there was no significant difference between the two groups. Augmented antiemetic effect of granisetron by concurrent therapy with a steroid was most notably demonstrated in male patients under 60 years of age. The antiemetic effect at the acute stage was proven to influence the final clinical effectiveness, thus suggesting the importance of antiemetic therapy of acute emesis. Adverse reactions were seen in two out of 122 patients (1.6%). They were slight headache and moderate diarrhea in 1 case each, both of which disappeared soon, confirming the high safety profile of granisetron.

After intravenous bolus injection of a camptothecin derivative, SK & F 104864 (topotecan), at 20 mg/kg into Sarcoma 180 bearing mice, the tissue concentration of total topotecan (SK & F 104864 plus SK & F 105992) in the mice decreased bi-exponentially, and the beta half-lives in most tissues were longer than those in plasma. The AUCs of total topotecan were extremely large in the kidney, that was followed by the pancreas > intestine > stomach > spleen > liver > thymus > lung > tumor > uterus > plasma. The concentration of total topotecan after 24 hours decreased to less than 2% of the peak level in most tissues except the kidney.

A camptothecin derivative, SK & F 104864 (topotecan), was injected for 30 minutes into the rabbit ear vein at a dose of 2 mg/kg or 5 mg/kg, and the plasma concentration was assayed by a HPLC method. The plasma level of SK & F 104864 (lactone form) decreased bi-exponentially with mean alpha and beta half-lives of 0.101 h and 0.849 h at 2 mg/kg, respectively, and 0.518 h and 7.57 h at 5 mg/kg, respectively. The AUCs were 0.846 micrograms.h/ml at 2 mg/kg and 2.14 micrograms.h/ml at 5 mg/kg. The plasma level of total topotecan (SK & F 104864 plus SK & F 105992) decreased bi-exponentially with mean alpha and beta half-lives of 0.696 h and 9.07 h at 2 mg/kg, respectively, and 0.795 h and 8.97 h at 5 mg/kg, respectively. The AUCs were 2.15 micrograms.h/ml at 2 mg/kg and 5.73 micrograms.h/ml at 5 mg/kg. The AUCs of lactone form were 39.3% of total topotecan at the 2 mg/kg dose and 37.3% at the 5 mg/kg dose, respectively. After intravenous bolus injection of SK & F 104864 at 20 mg/kg into Sarcoma 180 bearing mice, the alpha and beta half-lives of SK & F 104864 were 0.401 h and 3.99 h, respectively, and the AUC was 5.49 micrograms.hr/ml. The alpha and beta half-lives of total topotecan were 0.517 h and 4.27 h, respectively, and the AUC was 9.88 micrograms.hr/ml. The ratio of lactone form to total topotecan was 55.6%.

In vitro MTT assay was applied for examining chemosensitivity with 50 thyroid cancers; 47 papillary cancers, 1 follicular cancer, 1 anaplastic cancers, and 1 medullary cancer. Anticancer drugs examined were 5-fluorouracil (5-FU), cisplatin (CDDP), adriamycin (ADM), etoposide (VP-16) and ifosfamide (IFO) (active type). Their efficacy was as follows: 5-FU 0%, CDDP 40.9%, ADM 0%, VP-16 5.3%, IFO 48.5%. Anaplastic cancer and medullary cancer showed no sensitivity to all tested drugs. We compared the chemosensitivity between cancer tissue and normal tissue. CDDP was more effective in cancer tissue than in normal tissue. Chemosensitivity of CDDP depended on the drug concentration but 5-FU did not. CDDP and IFO might be useful against human differentiated thyroid cancer.

Some anticancer agents induce cell cycle arrest. We analyzed the effect of anticancer agents on cell-cycle regulators, such as CDK. Our data suggested that arresting cells in the G2-phase of the cell cycle by cisplatin might be regulated by dephosphorylation of cdc2 kinase. Butyrolactone I inhibits both cdc2 and CDK2 kinase in the cell-free system. The cytotoxic effect of paclitaxel shows mainly in the M-phase of the cell cycle. Suramin inhibits cdc2 kinase. UCN-01, a protein kinase-C inhibitor, also inhibits both cdc2 and CDK2 kinase. Some anticancer agents induce apoptosis.

Cell kinetics of cancers have been described in books, texts and other reports, but the correlation with action mechanism of antineoplastic agents has rarely been mentioned in the literature. The action mechanism of the antineoplastic agents such as interferon, ACNU and cisplatin was analyzed with use of propidium iodide and BrdU double staining by flow cytometer. Interferon showed S phase accumulation, ACNU and cisplatin blocked the stage of G(2)M phase. Flow cytometry was useful for the analysis of cell kinetics.

Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by the solvent evaporation method in an oil-in-oil emulsion system. When CDDP-MS was preserved in phosphate-buffer saline, the dissolution rate of cisplatin from CDDP-MS was 14% after one day, 25% after 5 days, 33% after 7 days, 66% after 21 days and 85% after 30 days. CDDP-MS and CDDP aqueous solution (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of cisplatin in 42 rats each. On days 0.5, 1, 5, 7, 14 and 21, omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of the CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Consequently, it was suggested that CDDP-MS is useful as a carrier in a drug delivery system, since it improves the burst effect and releases CDDP for a long time without serious side effects.

A new dosage formulation (MTX-CH), composed of fine activated carbon particles absorbing methotrexate (MTX), distributes concentrated MTX for long periods of time to the regional lymph nodes as well as to the injection site, in animal experiments. MTX-CH would enhance the therapeutic effects not only on the primary lesion but also on the lymphatic metastasis. As clinical trials, (A) in five patients with early gastric cancer, MTX-CH at 50 to 200 mg/person of MTX was injected endoscopically in and around the primary lesion before operation. Surgically removed specimens showed that three out of the 5 primary lesions had disappeared or were necrotic, and the remaining two lesions had shrunk. (B) Three patients with contraindication to surgery received the endoscopic injection of MTX-CH. The MTX-CH injected at 250 to 1,500 mg/person into and around the primary lesion of relatively early gastric cancer resulted in the complete disappearance of the primary lesions for 14 to 24 months up to the present time without enlargement of the lymph nodes. It was thought that local injection of MTX-CH will be effective therapy, especially for gastric cancer with potential lymphatic metastasis in patients with contraindications to surgery.

We attempted to mix an anticancer drug. MMC, with a fibrinogen preparation, Beriplast P (B. P.). First, we examined how MMC was gradually released from its mixture. As the result, its release depended on the MMC concentration in B. P., and the release rate of 1.0 mg MMC from 100 microliters B. P. was 1.6 mg/30 min. Second, we examined the safety of the conjugated drug for normal tissue, because MMC is one of anticancer drugs causing serious damage to normal tissue. When the conjugation of 100 microliters B. P. and below 1.6 mg MMC was coated within one square centimeter, the drug was safe for the endothelium of artery and vein, and the intestinal wall. Third, we attempted an experiment on both the antitumor effect and the role of survival prolongation of the conjugated drug in a mouse carrying a malignant tumor. MMC conjugated with Beriplast P had a highly antitumor effect, which caused necrosis in the cancer cells in unstable conditions. Also, its conjugation drug could inhibit the growth of cancer cells in stable conditions, and prolonged the survival period. From these results, the mixture of MMC and B. P. was found to possess an MMC releasing effect, was safe for normal tissues, and showed high antitumor effect with prolongation of the survival period.

We investigated the biochemical and molecular pharmacological parameters of fluorinated pyrimidines using malignant cells in pleural effusion or ascites from patients with malignant disease both before and after fluorinated pyrimidine chemotherapy, either systemically or intravesically. In four out of fifteen cancer patients, we could analyze the alteration of thymidylate synthase (TS) catalytic activity both before and after the treatment, showing that there was a decrease ranging 28% through 96.9%. We also analyzed a level of TS messenger RNA and TS protein using molecular biotechniques. None of these mutual correlations has so far been demonstrated, indicating that the data were analyzed through samples from patients not responding to the fluorinated pyrimidines. In a responding patient with advanced breast cancer, pre-treatment total TS protein was 130 fmol/mg and the TS activity was 3.27 pmol/mg/min. After intrapleural instillation of a combination of 5-FU 250 mg and leucovorin 3 mg, the total amount and the catalytic activity of TS could be measured. On the 11th day of treatment, the TS protein level decreased to 26 fmol/mg and the TS catalytic activity also decreased to 0.1 pmol/mg/min resulting in a TS inhibition rate of 92.3 percent. On the 17th day, the patient's malignant pleural effusion disappeared almost completely, suggesting that substantial TS inhibition may reflect the clinical evidence. This particular data showed that it would be predictable for clinical outcome to evaluate these parameters before and after fluorinated pyrimidine chemotherapy. Further study is warranted to evaluate the exact role of analyzing these parameters in clinical practice.

We examined the distribution of Lipo-CBDCA after intraperitoneal administration and antitumor effects in rats. The serum levels of platinum in Lipo-CBDCA were lower than in free-CBDCA intraperitoneal or intravenous administration at 15 and 30 min. after administration. After 3 hours, Lipo-CBDCA showed higher levels of serum platinum than free-CBDCA. These data showed the slow release of Lipo-CBDCA. The antitumor effects of Lipo-CBDCA were studied in rats with peritoneal dissemination due to AH 130 tumors. Intraperitoneal treatment with Lipo-CBDCA prolonged the life span significantly compared with Lipo-CBDCA. No side effects of chemotherapy were found in the liver, kidney, spleen or small intestine. A gastric cancer patient suffering from carcinomatous peritonitis with remarkable ascites was treated with Lipo-CBDCA intraperitoneally. After several injections of Lipo-CBDCA, the ascites disappeared completely and the CEA level of ascites decreased dramatically. These results indicate that intraperitoneal chemotherapy with Lipo-CBDCA may be more effective than free-CBDCA to manage carcinomatous peritonitis, and may be therapeutically useful without toxic side effects.

Sixteen patients with advanced breast cancer were treated with neoadjuvant intraarterial chemotherapy with high dose epirubicin. The following results were obtained: 1) Excellent down-staging effects were confirmed. Response rate of the primary tumor was 81.3%. 2) Leukopenia was the dose-limiting factor, and 81.3% of patients had WHO grade 2 or more leucopenia. However, the regimen was completed with supportive therapies. 3) At a median follow-up of 17 months, improved survival rates were noted. The present study showed the efficacy of neoadjuvant intraarterial chemotherapy with high dose epirubicin in the treatment of locally advanced breast cancer.

We treated 8 patients of Stage III and IV breast cancer preoperatively with THP-ADR intra-arterial infusion chemotherapy. The median dose was 200 mg with a range from 150 to 310 mg. The response rate of THP was 75.0% compared to 66.7% of ADR. Leucopenia was observed during THP treatment with a lower frequency of alopecia.

Plachitin is a chemical compound of cis-diammine-dichloroplatinum (CDDP) and chitin. Pharmacokinetics and adverse effects of Plachitin for intraperitoneal chemotherapy (IP) were studied in 11 patients who suffered from non-curative gastrointestinal cancers in comparison with 4 patients who underwent IP of CDDP. Five patients were given 300 mg (100 mg as CDDP) of Plachitin which was cotton type on the residual cancer mass (Group A). Six patients were given IP 300 mg of Plachitin particles (Group B). As the control group, 4 patients were given IP 100 mg of CDDP (Group C). The platinum concentrations of serum, urine and intraperitoneal discharge were observed during 3-4 weeks after the treatments and calculated as the CDDP concentration. The serum CDDP levels were below 0.1 micrograms/ml for 4 weeks in Group A and B. In Group A, urine concentrations of CDDP were significantly lower than in Group B and C at 3 and 5 days after the treatment statistically (p > 0.05). But at 14 days after treatment, the urine concentration of CDDP in Group A was higher than in Group C. In Group A and B, the CDDP concentrations of intraabdominal discharge was lower than in Group C statistically (p > 0.05). Nausea was observed only in one patient of Group B and other adverse effects which contained renal sufficiency were not recognized in the three groups. Thus, Plachitin was considered an effective and safe agent for intraperitoneal chemotherapy.

A clinical phase III study of tropisetron capsule was conducted to assess its efficacy, safety and usefulness on nausea and vomiting induced by carboplatin or non-platinum anti-cancer drugs. The study was conducted in patients who experienced vomiting on previous chemotherapy. Tropisetron 5 mg capsule was given to patients once 2 hours prior to the first administration of either carboplatin or non-platinum anti-cancer drugs; the patients were then observed for nausea and/or vomiting during 24 hours after the first administration. Some 56.7% (17/30) of the patients did not vomit after tropisetron administration, and the frequency of vomiting was significantly reduced compared with that during the previous chemotherapy. Further, in the clinical efficacy ratings, in which the efficacy was assessed on the basis of the nausea and vomiting data, 83.3% (25/30) of cases were rated as "effective or better". Adverse events observed were 3 cases of mild headache, but these were not clinically problematic. The above results reveal that tropisetron capsule is significantly effective and safe in the treatment of nausea and vomiting induced by carboplatin or non-platinum anti-cancer drugs; in addition, tropisetron proved to be highly useful for its convenience as an oral agent.

This paper describes tubulointerstitial changes of the kidney in association with a) pathophysiology of paraproteinuria and related disorders, and b) the management of leukemia and malignant lymphoma. Various forms of tubulointerstitial changes might be provoked following the accumulation of "abnormal macromolecules" In a), multiple myeloma, light chain cast nephropathy (myeloma kidney), AL amyloidosis, light chain deposition disease, macroglobulinemia, cryoglobulinemia etc. are briefly reviewed. In the majority of cases, leukemia and lymphoma do not manifest themselves as tubulointerstitial disorders. However, a large number of patients suffer from tubulointerstitial abnormalities in the course of and/or after receiving chemotherapy. Thus it is explained, in b), why treatment for hematological malignancy is apt to induce tubulointerstitial complications. In this context, drugs responsible for the development of tubulitis and/or interstitial fibrosis are briefly reviewed.