The effects of allopurinol (Allop) on the lipid peroxidation in the nephrotoxicity of an antitumor drug, cisplatin (CDDP) were studied in mice. CDDP was administered intraperitoneally to two groups (CDDP + Allop group and CDDP + CMC-Na group) at single doses of 10 mg/kg, and mice were sacrificed 3 days after CDDP administration. The body weights of the CDDP-administered group gradually decreased to approximately 78% of the values of the control group (saline + Allop group and saline + CMC-Na group) within 3 days. Plasma urea nitrogen and creatinine, especially in the CDDP + Allop group, increased after 3 days. Lipid peroxides in the blood and kidney were monitored by measuring the production of malondialdehyde (MDA), which increased in the CDDP + CMC-Na group. On the other hand, MDA levels in the CDDP + Allop group increased in the kidney but remained unchanged in the blood. Changes were observed in tissue glutathione (reduced form, GSH; oxidized form, GSSG) levels in the CDDP + Allop group but not in the CDDP + CMC-Na group. Histomorphological examination demonstrated the degeneration of the proximal tubuli in the CDDP-administered groups. Especially in the CDDP + Allop group, the increase of mesangium cells in the glomeruli was observed. From these results, it was suggested that Allop was not able to inhibit CDDP-induced lipid peroxidation in the kidney, and the kidney function became more severely impaired by the administration of Allop.

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.

We studied the antitumor activity of newly synthesized dolastatin 10 analogs. TZT-1027 showed remarkable activity and was selected for further development. TZT-1027 was found to inhibit the assembly of porcine brain microtubule proteins and to depolymerize the polymerized microtubule proteins. Therefore, its mechanism of antitumor activity seems to be at least partially ascribed to the inhibition of microtubule assembly. We further studied the binding site of TZT-1027 on tubulin. Scatchard analysis of 3H-TZT-1027 binding data suggested two binding sites including a high affinity site and a low affinity site. TZT-1027 affected the binding of vinblastine (VBL) on tubulin but its binding site isn't identical to the VBL binding site. TZT-1027 induced apoptosis within 24 h, not only in human leukemia cells such as HL-60, but also in solid tumors such as human prostate carcinoma cells DU145 and human mammary carcinoma cells MCF-7. TZT-1027 showed good antitumor activity against human xenografts (MX-1 and LX-1) without causing serious body weight reduction, which resulted in tumor regression. We examined the effect of TZT-1027 on the established tumor vasculature using the dye perfusion into tumor. TZT-1027 exhibited considerable antivascular activity in tumor sections in addition to excellent cytotoxic effect.

Pectenotoxin-2 (PCTX-2), which is one of Diarrhetic Shellfish Poisoning (DSP), is a family of cyclic polyether macrolide toxin isolated from scallop Patinopecten yessoensis. Although PCTX-2 has a potent cytotoxic activities against several cancer cell lines, the biochemical activity of PCTX-2 has not been determined yet. To clarify the biochemical activity of PCTX-2 is the aime in this study. PCTX-2 inhibited the contractions elicited by 72.7 mM KCl or 1 microM phenyrephrine in a concentration dependent manner in the isolated rat aorta. In A10 cells, actin stressfiber in center but not in periphery of the cell was disrupted by PCTX-2 without any visible shape change. By monitoring fluorescent intensity of pyrenyl-actin, PCTX-2 was found to inhibit the velocity and the degree of actin polymerization in a concentration dependent manner. In addition, PCTX-2 decreased viscosity of F-actin measured with falling ball viscometry. Stoichiometric analysis indicated that PCTX-2 forms 1:4 complex with G-actin. These results suggest that PCTX-2 is a potent natural actin depolymerizing compound with unique mode of action.

Combination therapy using HCFU and TNP 470, which inhibits angiogenesis, was examined for effectiveness against the footpad injection model of LMFS tumor. This LMFS, a retroperitoneal sarcoma of BALB/c mice, proliferated at the inoculation site (100% take) and all mice operated on after day 15 had spontaneous metastatic nodules in the liver. Mice with the LMFS tumor were given HCFU and 5-FU (5 days/week), and/or TNP 470 (3 days/week) from day 3 for 3 weeks and sacrified at day 28 under anesthesia. Seven of 10 mice receiving 5-FU and TNP 470 died from the side effects of the drugs. Mean tumor weight and liver metastatic nodules were determined and compared with a control group. The results were as follows: HCFU group: 94.6%, 11.8%, 5 FU group: 73.9%, 28.8%, TNP 470 group: 67.6%, 44%, HCFU and TNP 470 group: 33.3%, 6.4%. Mice with LMFS were given HCFU and/or TNP 470 from day 3 for 4 weeks. The foot on the injected side was amputated on day 15, and the animals were sacrified on day 35. Liver metastatic nodules compared with those of the operation (OP) group as follows: OP + HCFU group: 14.4%, OP + TNP group: 39.1%, and OP + HCFU + TNP 470 group: 5.4%. Histologically, 5 of 5 mice of the OP group, 3 of 5 of the OP + HCFU group, 4 of 5 of the OP + TNP 470 group and 1 of 5 of the OP + HCFU + TNP 470 group had liver metastases. These results show that while either HCFU or TNP 470 is effective by itself, a combination of these drugs is more effective against liver metastasis.

Clinically distinct features in both alkylating agents--and topoisomerase II (topo II)-induced secondary leukemias (SL) are reviewed with special reference to the increasing frequencies observed in relation to advances in modern cancer chemotherapy. Topo II interacts with, and then stabilizes the cleavable complex that ultimately results in double strand breaks. In patients with SL, breakpoints in MLL gene are clustered within SARs of 3' bcr. However, mechanisms by which the former type of SL is caused remain to be elucidated. Since alkylating agents often induce profound marrow dysplasia, long-lived lesions induced on hematopoietic stem cells are of potential relevance to the development of SL. This process may be partially demonstrated by the variety of mitotic modifications found in MDS. Recently, the association has been investigated between certain enzyme polymorphisms related to activation or detoxification of anticancer agents and SL. These studies have potential importance, since individuals with a certain genotype may be at increased risk for SL.

Due to the innovations in various aspects of cancer therapy, the time has come when more than half of cancer patients survive 5 years. However, secondary cancer, especially leukemias arising among the survivors and threatening their lives, has become a serious problem. In the present paper I focus on chemotherapeutics, especially DNA topoisomerase II inhibitors such as etoposide and adriamycin, presumed to be the causative agents, and their mode of intervention in the catalytic action of this enzyme. I describe the molecular basis of chromosomal translocations inherent in therapy-related secondary leukemias, and present a hypothesis for the molecular mechanism underlying the occurrence of the disease; namely, that poison-type topoisomerase II inhibitors stabilize the reaction intermediate covalent enzyme-DNA cleavage complexes, called "cleavable complexes," which in turn trigger the mobilization of various DNA damage repair and recombination systems to cope with the damage. The recombinant which acquires a growth advantage over others then overproliferates to become the leukemogenic population.

Tropisetron is used as an anti-emetic agent against chemotherapy-induced nausea and vomiting. Tropisetron shows strong 5-HT3 antagonist and weak 5-HT4 antagonist activities in vitro. In the various animal models of vomiting including chemotherapy- or radiotherapy-induced emesis in the dog and ferret, tropisetron is reported to inhibit the emetic episodes. The potent anti-emetic activity of oral tropisetron rather than the i.p. administered drug suggests that it can act directly from the intestinal lumen as well as from the blood stream after its absorption. Moreover, the anti-emetic activity of tropisetron may involve the 5-HT4-receptor mechanism in addition to the 5-HT3-receptor mechanism. Tropisetron has several pharmacological activities other than anti-emesis such as the stimulation of the gastric emptying and the inhibition of the diarrhea, visceral pain and anxiety. These effects of tropisetron may contribute to the high clinical efficacy of tropisetron against chemotherapy-induced emesis.

As a part of studies to clarify the efficacy mechanism of carmofur (HCFU), a 5-FU analog, the degree of cross-resistance to HCFU of cell lines of cultured human colon cancer DLD-1 and a stomach cancer NUGC-3, both of which had acquired resistance to 5-FU, was studied in vitro and in vivo. In vitro, both resistant cell lines showed no or little cross-resistance to HCFU under a short-term drug exposure, and very low cross-resistance to HCFU, as compared to resistance to 5-FU, under a long-term drug exposure. In therapeutic experiments using nude mice bearing parent or subcutaneously transplanted 5-FU-resistant DLD-1 cells, HCFU exerted almost the same growth-inhibitory effects on both tumors. These results suggest that HCFU itself may have its own anti-tumor mechanism, different from that of 5-FU.

We examined the antiangiogenic and antitumor efficacy of a newly-developed matrix metalloproteinase (MMP) inhibitor, BPHA (N-biphenyl sulfonyl-phenylalanine hydroxiamic acid). BPHA potently inhibits MMP-2, 9 and 14 but not MMP-1, 3 or 7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMP tested. Daily oral administration of BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth and liver metastasis, whereas (-)BPHA did not. These results demonstrate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential without hematotoxic effect or loss of body weight.

Progress in the genetic and molecular elucidation of the pathogenesis of cancer metastases has led to the identification of important molecules such as growth factors, signal transducing molecules, angiogenic factors, adhesion molecules and matrix metalloproteinases, which can be now target molecules for antimetastatic therapy. Many drugs designed and developed to therapeutically control such metastasis-related molecules are now in the clinical study stage. This paper reviews the recent progress of ongoing clinical trials in the U.S.A. and Europe.

Recently, the chemopreventive effects of various drugs on N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced rat urinary bladder carcinogenesis have been reported. The aim of this study was to evaluate the effect of liarozole, an antitumor agent that inhibits the metabolism of retinoids, on the initial stage of BBN induced rat urinary bladder carcinogenesis.

Our previous mouse experiment showed intraperitoneal administration of CPT-11 was more effective not only for peritoneal seeding but for liver metastases than intravenous administration of CPT-11. We studied tissue concentrations of the liver when CPT-11 was administered intraperitoneally or intravenously for ICR mice. Mice liver was resected at 15 min, 1, 2, 4, 8 and 26 hours after intraperitoneal or intravenous administration of 40 mg/kg CPT-11. CPT-11, SN-38 and SN-38 GLU were measured with HPLC. The liver concentration of CPT-11 at 15 min after intravenous administration was higher than after intraperitoneal administration. A higher liver CPT-11 concentration was prolonged in the intraperitoneal administration group. No differences were demonstrated in the concentrations of SN-38 and SN-38 GLU between i.p. and i.v. groups.

The effect and drug absorbtion of intrabiliary chemotherapy with Doxorubicin for pancreaticobiliary cancer with PTCD was investigated. Doxorubicin (DXR: 20 mg) was administered intrabiliary for 3 hours by PTCD catheter. Radiographic evaluation of the bile duct before and after chemotherapy and measurement of DXR concentration in the serum and bile were carried out.

We have investigated the efficacy of intraperitoneal or intrathoracic administration of hydroxyapatite particles (HAp) loaded carboplatin (CBDCA). HAp-CBDCA (HAp; 200 mg, CBDCA; 4 mg) was administered intraperitoneally to rats with peritoneal carcinomatosis. The area under the curve of the ascitic platinum (Pt) increased significantly with rats given HAp-CBDCA, and the omental Pt levels in the HAp-CBDCA group remained higher and longer. Additionally, the HAp-CBDCA group showed a trend toward longer survival when compared with the CBDCA alone group. In clinical use, HAp-CBDCA (HAp; 5 g, CBDCA; 150 mg) was administered intrathoracically to a patient who had undergone esophagectomy. The Pt in serum was detected until 7 days after administration of HAp-CBDCA.

Fifteen patients with liver metastases of colorectal cancer were entered in our study, and 5-FU was given continuously by hepatic intra-arterial route at 1 g/day over 6 days. No leukopenia (< 3,000/mm3), anemia (< 10 g/dl), or thrombocytopenia (< 75,000/mm3) occurred, and no elevation of serum AST (> 150 IU/l) or serum T-Bil (> 2 mg/ml) appeared. One patient (4.2%) had nausea with vomiting 1-5 per day, and another (4.2%) had mucositis requiring treatment. In patients with multiple liver metastases, survival of the continuous infusion group [total dose of 5-FU > or = 12 g] (n = 5) seems to be longer than those of the hepatectomy only group (n = 3) or the control group (n = 7). We suggest that this continuous intra-arterial infusion of high-dose 5-FU is a useful chemotherapy with few side effects or complications.

Navelbine is a derivative of vinca alkaloid that interferes with tubulin assembly and exhibits antitumor activity. Clinical trials with single-agent Navelbine proved it to be effective against non-small cell lung cancer (NSCLC), breast cancer, and other tumors. At present, clinical trials by combination with various drugs are ongoing NSCLC and breast cancer. Navelbine+cisplatin is considered to be a standard therapy for NSCLC in Europe and SWOG. In breast cancer, the combination chemotherapy of Navelbine with anthracyclines, 5-FU, and other agents has been reported to be effective. The main adverse reactions caused by Navelbine are leukopenia and neutropenia. It causes less nerve neuropathy than vindesine. As Navelbine is a central therapeutic drug in combination therapy for NSCLC, more effective combination therapy with it are expected to be developed.

Cancer cachexia is a common paraneoplastic syndrome in patients with advanced malignancies. However, the mechanisms of the development of cancer cachexia remain to be elucidated. Interleukin (IL)-6 is known to be involved in the development of cancer cachexia. The KPL-4 human breast cancer cell line, which was recently established in our laboratory, secretes IL-6 into the culture medium. Oral administration of doxifluridine (5'-DFUR, 60 mg/kg or 120 mg/kg) significantly inhibited the growth of KPL-4 tumors, reduced the tissue levels of IL-6, and alleviated body weight loss. Serum IL-6 levels were also lowered by 5'-DFUR in nude mice bearing KPL-4 tumors. Additionally, it is suggested that tumor necrosis factor (TNF)-alpha is involved in the cachexia induced by KPL-4 tumors. We suggest that 5'-DFUR suppresses cancer cachexia by lowering IL-6 levels in the tumor tissues and serum.

A pharmacological comparison of weekly administrations of docetaxel (TXT) and standard/conventional TXT was carried out among patients with metastatic breast cancer. Fifteen patients were enrolled in this study of weekly TXT (TXT: 40 mg/body/week x 3 with 1 week interruptions in 10 patients) and standard TXT (TXT: 60 mg/m2/3 weeks in 5 patients). The median dose intensity (DI) of weekly TXT (20.63 mg/m2/week) was similar to that of standard TXT, and the median relative dose intensity (RDI) of weekly TXT was 0.98. The median area under the plasma concentration-time curve (AUC) of weekly TXT (1.20 micrograms.h/ml) was smaller than that of standard TXT (1.87 micrograms.h/ml). Therefore, there were remarkable decreases in both median percent of decrease in neutrophil counts and grade 3, 4 neutropenia with weekly TXT. These pharmacological data show that weekly TXT is a well-tolerated and feasible schedule for the treatment of metastatic breast cancer.

A 47-year-old female underwent mastectomy after neo-adjuvant chemotherapy including an anthracycline agent for advanced breast cancer. She developed a pleural metastasis on 16 months later, which was refractory to intrathoracic cisplatinum administration and intravenous Docetaxel therapy. Brain metastases were also found. We therefore treated her with whole brain radiation therapy and oral chemotherapy with 5'-DFUR and cyclophosphamide. This combination therapy produced a marked decrease in each metastasis. The adverse effects were not remarkable. This regimen may play an important role not only from the standpoint of its effectiveness against tumor growth but also the quality of life of the patient.