Takao Hattori

Phase I study of recombinant human tumor necrosis factor

SummaryA phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x105 units/m2. The dose was escalated up to 16x105 units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x105 units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x105 units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x105 units/m2.

Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas

SummaryDNAs from 37 human gastric carcinomas and seven lymph node metastases were analyzed for alterations of the epidermal growth factor receptor (EGFR) gene and oncogenes by the Southern blot hybridization method. The probes used were EGFR gene, c-Ha-ras, v-Ki-ras, N-ras, c-myc, v-myb, v-fos, c-erbB-2, v-erbA, v-abl and v-fes. Amplification of the EGFR gene was detected in only one poorly differentiated adenocarcinoma. Amplifications of c-myc gene and c-erbB-2 gene were each observed in two well differentiated adenocarcinomas. One of these tumors had coamplification of c-erbB-2 and c-erbA genes but there were no amplifications nor rearrangements of other oncogenes. The poorly differentiated adenocarcinom with amplified EGFR gene also showed enhanced expression of EGFR gene by Northern blot analysis and additionally had strong synchronous immunoreactivity for EGFR and EGF.

Relationship between epidermal growth factor receptor status and various prognostic factors in human breast cancer

Relationship between epidermal growth factor receptor (EGFR) status and various prognostic factors was investigated in 91 human breast cancer tissues. Epidermal growth factor receptor was measured by biochemical competitive binding assay using iodine 125 epidermal growth factor (125I)‐EGF. The EGFR status was not correlated with axillary lymph node involvement, tumor size, stage, and histologic type, but significantly correlated with histologic grading (P < 0.05) and lymphatic invasion (P < 0.01). Between EGFR and estrogen receptor (ER) status, a clear inverse relationship was observed (P < 0.01). The Ki‐67‐positive stained cell rate, which reveals the proportion of cycling cells, was significantly higher in EGFR‐positive tumor tissues than in EGFR‐negative cases. Furthermore, preliminary postoperative survey demonstrated a high tendency of recurrence rate of patients with EGFR‐positive tumors as compared with those with EGFR‐negative tumors. These data suggest that EGFR status may be important for the prediction of biologically high malignant potential.

Postoperative adjuvant chemotherapy for gastric carcinoma analysis of data on 1805 patients followed for 5 years

The effectiveness of combination chemotherapy with mitomycin‐C (MMC) plus Futraful (N1‐(2′‐tetrahydrofuryl)‐5‐fluorouracil) for gastric cancer was investigated in a prospective randomized and controlled study. Two thousand sixty‐four Japanese patients in 297 hospitals were entered, and 1805 could be followed. All patients had undergone gastrectomy from May 1975 to July 1976. These patients were grouped into two protocols: protocol I (intermittent intravenous injection of a moderate dose of MMC), and protocol II (bolus intravenous injection of MMC), each of which was allocated to group A (without Futraful) and group B (MMC plus oral administration of Futraful for 3 months). Statistically, this randomized study showed that the 5‐year survival rate of patients with advanced cancer was not enhanced. However, with protocol II the Futraful administration seemed to improve the 5‐year survival rate for those with Stage III cancer and for those with positive lymph node metastasis plus obvious serosal invasion.

Clinical Efficacy of Lentinan on Neoplastic Diseases

Lentinan, a β-(1-3)-glucan with some β-(1-6)-gluco-pyranoside branchings, has been extracted and purified from Lentinus edodes a most popular edible mushroom in Japan. This substance has been shown to act as an immunostimulating agent through host defense mechanisms as reported by Chihara et al (1, 2). Lentinan exerts it’s antitumor activity on both syngeneic and spontaneous tumors. The cellular mechanisms of antitumor activity have been clarified by Hamuro et al (3), in that lentinan appears to stimulate host defense mechanisms to induce cytotoxic T cells, natural cytotoxicity and/or augmented macrophages against tumor cells. This suggests that lentinan may be effective for patients with malignant diseases. Based on the results of Phase I and II clinical trials conducted by Taguchi et al (4), the administration conditions for lentinan have been determined to be intravenous administration at doses of 0.5 to 1.0 mg/person/day once or twice a week in combination with chemotherapeutic agents for patients with advanced or recurrent cancer. In order to clarify the clinical efficacy of lentinan administration a Phase III randomized control trial has been conducted on patients with advanced or recurrent gastric or colorectal cancer.

Postoperative adjuvant immunochemotherapy with mitomycin C, futraful and PSK for gastric cancer. An analysis of data on 579 patients followed for five years.

In order to evaluate the combination of immunochemotherapy with mitomycin C (MMC), futraful (FT) and PSK, as an adjuvant to surgery for curatively resected gastric cancer, a randomized controlled study by the sealed envelope method was performed with the participation of 97 hospitals in the Kyushu and Chugoku districts of Japan. The MMC+FT+ PSK group showed a significant increase in 5 year survival from the other groups (p<0.05). Moreover the survival rate was significantly higher in the MMC+FT+PSK group than in the MMC+FT group (p<0.01). According to the analysis on stratification, the MMC+FT+PSK group showed the best survival rate in cases with positive lymph node metastases, positive serosal invasion and positive lymph node metastases plus serosal invasion, and in cases of undifferentiated carcinoma by histological type and in those with a preoperative positive PPD reaction (p<0.01 or p<0.05). Thus, the combination of MMC, FT and PSK was indicated to be useful as an adjuvant immunochemotherapy for those patients with gastric cancer submitted to curative resection.

Postoperative adjuvant chemotherapy for gastric cancer, the second report. Analysis of data on 2873 patients followed for five years

The effectiveness of combination chemotherapy with mitomycin-C (MMC) plus futraful (N1-(2′-tetrahydrofuryl)-5-fluorouracil), as an adjunct to surgery for gastric cancer was investigated in a prospective randomized controlled study. Three thousand and thirty-three Japanese patients in 344 hospitals were entered and 2873 could be followed for 5 years. All patients had undergone gastrectomy from April 1977 to May 1979 and were assigned, at random, to either Groups A, B or C. In Group A, bolus MMC was administered with no further treatment. In Group C, oral futraful was given for one year, without MMC induction. In Group B, both a bolus MMC injection and oral futraful were prescribed. This randomized study showed no statistical difference in the 5 year survival rate among the three groups. However, in patients given MMC and put on oral futraful for one year, the 5 year survival rate for those with stage III gastric cancer or for those with positive lymphnode metastasis plus obvious serosal invasion seemed to be improved.

Concanavalin A-induced and spontaneous suppressor cell activities in peripheral blood lymphocytes and spleen cells from gastric cancer patients

In 173 gastric cancer patients, activities of Concanavalin‐A‐induced suppressor cells (Con‐AS) and spontaneous suppressor cells (SpS) in peripheral blood lymphocytes (PBL), splenic vein lymphocytes (SVL), and spleen cells (SCs) were investigated. Suppressions by Con‐AS in PBL were significantly effective in patients of Stages III and IV, while suppressions by SpS were effective in patients with recurrent tumors. Thus, in PBLs of cancer patients, suppressor precursors, which are considered to be activated in vitro by Concanavalin‐A, seemed to appear with the advances of the disease, and SpS activities, which could be already activated in vivo, seemed to increase in the terminal stage. In SCs, increased activities of Con‐AS, but normal activities of SpS, were observed, and these suppressor‐cell populations consisted of glass nonadherent cells. Suppressor activities of SCs would be due to suppressor T‐cells, not to other types of cells. Furthermore, Con‐AS existed in the medium‐sized lymphocytes, which were fractionated on the basis of cell size, while SpS in the large‐sized lymphocytes. A higher proportion of T‐cells, bearing Fc receptors for IgG, was observed in the larger‐sized lymphocyte fractions. Cell numbers in the large‐sized lymphocyte fraction tended to increase with the advances of tumors. From these results, it is suggested that higher presence of suppressor precursors and the increase of SpS activities may occur in cancer patients, depending on the tumor advancing.

Post-operative long-term adjuvant immunochemotherapy with mitomycin-C, PSK and FT-207 in gastric cancer patients.

Long-term adjuvant immunochemotherapy carried out on the gastrectomized patients with stomach cancer was reported. The protocol comprises the administration of large-dose of Mitomycin-C (20+10) mg just after gastrectomy and the long-term administration of PSK, FT-207 or (PSK+FT-207). Almost no side effects were observed. According to the studies on the immunological parameters, the increased reactions in PPD skin test and lymphocyte blastogenesis induced by PHA and PWM were observed remarkably in group (P+F) 3 or 6 months after gastrectomy. As for the survival rate, group (P+F) showed the most preferable results at one year in stage IV, at two years in stage III and at three years in all the stages, respectively after gastrectomy.

Detection of androgen receptors in human esophageal cancer

The incidence of esophageal cancer is much higher in men than in women and the prognosis is generally worse in men than in women. This seems to depend on the difference in the hormonal environments of the patient. In this paper, androgen receptors (AR) were measured in 21 cases of human esophageal cancer. Of these, two cases of esophageal cancer xenografts implanted into nude mice were AR positive. In EH-1, an established cell line from human esophageal cancer, the number of binding sites was increased and tumor growth was enhanced by testosterone administration. On the other hand, the number of binding sites was decreased and tumor growth was suppressed by castration. The administration of estrogen, however, did not inhibit tumor growth.