Iwao Yoshizaki

A molecular biological study of anti-tumor mechanisms of an anti-cancer agent Oxaliplatin against established human gastric cancer cell lines

We report that preoperative administration of Oxaliplatin, a new anti-cancer platinum agent, is an effective treatment for gastric cancer. The purpose of this in vitro study is to determine whether Oxaliplatin induces apoptosis in established human gastric cancer cell lines. Five established gastric cancer cell lines are used: MNK45, KATO-III, OKAJIMA, MNK28 and MNK74. Chemosensitivity to l-OHP is studied using a growth inhibition test. Induction of apoptosis in gastric cancer cells is analyzed by assessing DNA ladder formation, DNA fragmentation and actin cleavage. While all five gastric cancer cell lines are sensitive to Oxaliplatin, the poorly differentiated lines are the most sensitive. DNA ladder formation and/or DNA fragmentation are detected in all gastric cancer cell lines. However, actin cleavage is not detected in any of the cell lines. Oxaliplatin has an anti-cancer effect on human gastric cancer cell lines, particularly cell lines of poorly differentiated adenocarcinoma, indicating that Oxaliplatin would be an effective treatment for poorly differentiated gastric cancer. Oxaliplatin induces apoptosis in gastric cancer cell lines, but actin cleavage is not detected in cancer cells. This finding suggests that (1) the apoptotic caspase pathway leads mainly to DNA condensation and fragmentation, and (2) caspase-independent apoptotic pathways may be activated when gastric cancer cells are treated with Oxaliplatin.

Pilot study for preoperative administration of 1-OHP to patients with advanced scirrhous type gastric cancer

A new DACH platinum complex, l-OHP, was developed by Kidani as an anticancer agent. A clinical trial took place in Europe which demonstrated its therapeutic efficacy for colorectal cancer. An effective treatment, especially chemotherapy for patients with a advanced scirrhous type gastric cancer, has not yet been established. An in vitro study showed that l-HOP inhibited cell growth in human gastric cancer cell lines. Our pilot study determined the efficacy of preoperative administration of l-OHP, 67 mg/m2 to 100 mg/m2, every 2-3 weeks, for two to three cycles, in five patients with this disease (Stage III and IV) roentogenoscopically and histologically. The platinum concentration in the tissues was also measured. By X-ray examination of the stomach at the time of pre- and post-administration of l-OHP, extension of the lesional gastric wall was observed. Histologically three Grade 2 responses and two Grade 1a responses were obtained according to the criteria presented by Japanese Research Society for Gastric Cancer. The mean platinum concentrations in the lesional tissues were 0.98 ppm and 0.5 ppm in the patients administered l-OHP for three and two cycles respectively. There was no toxicity that prevented surgery. These preliminary results showed the possibility that 1-OHP would be effective for patients with advanced scirrhous type gastric cancer as a neoadjuvant therapy.

Inhibition of growth of human breast cancer cells in culture by neutron capture using liposomes containing 10B

Cell destruction in boron neutron capture therapy is effected by nuclear reaction between 10B and thermal neutrons with the release of alpha-particles (4He) and lithium-7 ions (7Li). 4He kills cells within 10 microm of the site of 4He generation, therefore it is theoretically possible to destroy tumour cells without affecting adjacent healthy tissue, given selective delivery of compounds containing 10B. Liposomes wore prepared by vortex dispersion of solutions containing 10B compounds with dried lipid films and the effects of those compounds on human breast cancer cells in culture were examined after thermal neutral irradiation. [3H]-TdR incorporation by MRKnu/nu-1 cells treated with 10B-containing liposomes showed 40% suppression compared with liposomes without 10B, at 2 x 1012 n/cm2 thermal neutron fluence. Inhibition of tumour cell growth with liposomes prepared with 100 mm 10B-compound was as significant as with those made with 500 ppm 10B solution. The concentration of 10B in liposomes was 76.5 +/- 3.4 microg/mL. Boronated liposomes can thus deliver sufficient 10B atoms to this line of breast cancer cells in culture to effect cytotoxicity and suppression of growth after thermal neutron irradiation.

Docetaxel alone or orally combined with 5-fluorouracil and its derivatives: effects on mouse mammary tumor cell line MM2 in vitro and in vivo.

Although docetaxel (Taxotere; TXT), a taxoid anticancer drug, is clinically and experimentally very effective against breast cancer, its antitumor effect is of very short duration. We addressed whether 5-fluorouracil (5-FU) and its derivatives can act synergistically with TXT against mammary tumors, with placing particular stress on their use by oral route. Mouse mammary tumor cell line, MM2, was propagated in culture and as ascites in mice. Carmofur (HCFU) and doxifluridine (5′-DFUR) were used as 5-FU derivatives. In vitro, the cytotoxic effects of antitumor drugs on MM2 cells were examined by MTS assay. In vivo, mice inoculated i.p. with MM2 cells were treated with i.p. injection of TXT and/or oral administration of 5-FU or its derivatives, and observed for curing tumor. In vitro, the synergistic effects were observed in the combination of TXT and 5-FU or HCFU, but not in that of TXT and 5′-DFUR. In vivo, all of these combinations cured tumors far more effectively than TXT alone. The discrepant result of the combination of TXT and 5′-DFUR between in vitro and in vivo was ascribed to up-regulation of pyrimidine phosphorylase in tumor cells in vivo by TXT. Thus, 5-FU, its masked compounds like HCFU and its prodrugs like 5′-DFUR can act synergistically with TXT in the therapy of cancer even when administered by the oral route.

Inhibition of Human Pancreatic Cancer Growth by the Adenovirus-Mediated Introduction of a Novel Growth Suppressing Gene, tob, In Vitro

Tob (Transducer of ErbB-2) is a newly identified tumor suppressor that may interact/interfare with protein tyrosine kinase receptors including ErbB-2 [1]. ErbB-2 phosphorylates and interacts with Shc that participates inbetween active tyrosine protein kinases to Ras signaling pathway. A point mutation or an elevated expression of ErbB-2 results in oncogenic growth of cells.

Correlation between timing of surgery in relation to the menstrual cycle and prognosis of premenopausal breast cancer patients

The timing of surgery in relation to menstrual phase might affect the progress of disease in premenopausal women with operable breast cancer. In the present study, the records were examined of 28 such cases treated between 1990 and 1999, and compared for recurrence-free survival with reference to the phases of the menstrual cycle defined by Hrushesky and Senie. During the follow-up period, breast cancer relapse occurred in five patients, and one patient died of another disease unconnected with recurrent breast cancer. The recurrence rate was not significantly different between two phases classified by either Hrushesky or Senie. However, patients with early-stage breast cancer operated during the perimenstrual phase and those with advanced breast cancer which was resected during the peri-ovulatory phase appeared to have a better prognosis than patients operated on during the other phases. Since the prognosis for breast cancer patients is dependent not only on the menstrual cycle but also on many other factors, it is concluded that the menstrual cycle cannot constitute an absolute prognostic factor.

Diagnosis of peripapillary carcinoma: endoscopic findings

During the period 1982-1988, 8 patients were admitted with peripapillary carcinoma. Pancreatico-duodenectomy (PD) was successfully carried out on 7 occasions but only 3 patients are alive today. Early diagnosis of this disease is therefore mandatory. Endoscopic sphincterotomy is particularly useful for the diagnosis of the non-exposed type of carcinoma in the peripapillary region.