590-S (1-phthalidyl-5-fluorouracil) is a derivative of 5-fluorouracil and shows a several characteristics in experimental studies. That is, good absorption from the intestine, high blood levels of 5-fluorouracil, its rapid clearance, low toxicities, excellent tumor inhibition and broad anticancer spectrum, etc. From preliminary studies and phase I studies, MTD is thought to be 750-800 mg/m2 in daily administration. Mild G.I. toxicities was encountered in a few cases. However, CNS toxicities were not experienced in any of our cases.

The properties of Porphyrin and Pheophorbide derivatives with cyclic tetrapyrrole structure have a specific character to accumulate selectively in tumor tissues and destruct tumor cells by photodynamic action. Recently, Photoradiation therapy of cancer with Porphyrin derivatives has put into practice, but its indication is very limited. We examined fundamentally on tumor tissue affinity of various Porphyrin and Pheophorbide derivatives, aiming at expanding therapeutic indication and application. As materials we used 73 derivatives in total, including 14 Porphyrin derivatives, 32 Pheophorbide derivatives, 17 Porphyrin metal complex and 10 Pheophorbide metal complex, and examined about the relation between their side branches and their tumor tissue affinity by N2-pulsed Laser spectrofluorometry, using tumor-bearing Golden Hamster. Furthermore, we investigated substances connected with Hematoporphyrin derivatives (HPD) in tumor cells. As a result, we had the following conclusions. N2-pulsed Laser spectrofluorometry is useful for analysis of Porphyrin and Pheophorbide derivatives in vivo. In Porphyrin derivatives, those with dimer structure and acetyl radical have higher tumor tissue affinity than those without such structures. Existence of OH radical and dimer structure is dispensable for tumor tissue affinity of Pheophorbide derivatives. OH radical in Porphyrin metal complex and acetyl radical in Pheophorbide metal complex are important factors for tumor tissue affinity of them. It is suggested that Hematoporphyrin derivatives (HPD) in vivo combine with protein in tumor cells.

In vitro tests were performed to assess the sensitivity to six anticancer agents-ACT-D, ADM, CDDP, CQ, 5-FU and MMC-of a JOHYL-1 (ascites type) cell line from human dysgerminoma which was used as challenge strain. For comparative assessment, anticancer sensitivity was expressed as the ratio of IC50 and IC90 to LD50 (i.v.) in mice. Drug dose-response and time-response curves were plotted, and the IC50 ratio was calculated, for each test compound in order to investigate the mechanism of anticancer action. The results obtained were as follows. CQ proved to be remarkably active and ADM fairly active against JOHYL-1 (ascites), but 5-FU, CDDP and MMC varied remarkably with the parameter of measurement employed. Analysis of IC50 ratio data and patterns of cell growth inhibition indicated the growth-inhibitory effect of CDDP to be concentration-and time-dependent. The results of the present study are in close accord with the pattern of action reported in the literature.

In a randomized controlled study, the efficacy of MCNU was compared with that of Busulfan in 95 patients with chronic myelogenous leukemia. Of the patients studied, 95 were entered among whom 77 were evaluable. These comprised 40 for an MCNU group (M) and 37 for a Busulfan group (B). No significant difference was found statistically between the two groups with regard to background factors, i.e., male-to-female ratio, age, white blood cell counts, platelet counts, splenomegaly or Ph1 chromosome.

5'-Deoxy-5-Fluorouridine is converted to 5-Fluorouracil by pyrimidine nucleoside phosphorylase of which activity is higher in tumor tissues than in surrounding normal ones. The interim result of the phase II study of this drug showed an efficacy in breast, gastric, colorectal and head & neck cancers. Above all, some CR cases in breast cancer indicated remarkable superiority of this drug for monotherapy. The duration of response was relatively long. Even in the cases with previously negative fluorinated pyrimidine therapy, this drug showed a considerable response rate. The main side effect was diarrhea but it was controllable. Diarrhea would become a good indication for determining continuation or cessation of the treatment with this drug.

A randomized controlled trial was made to compare the therapeutic result of oral high-dose medroxyprogesterone acetate (HD-MPA) versus mepitiostane (MS) in the treatment of postmenopausal breast cancer. MPA (1200 mg) was given p.o., b.i.d. to 47 patients and produced objective response in 19 of them (40.4%). Objective response was seen in 14 of the 40 control patients given MS p.o., b.i.d. (35.0%). Among patients with bone metastases, 6/19 (31.6%) for HD-MPA and 2/23 (15.4%) for MS showed objective response. The other merits of HD-MPA suggested in the study were improvement in performance status, anabolic effect and myeloprotective effect.

A clinical phase II study of TK-117, one of the derivatives of FUDR, was performed in 18 patients with gastric cancer by our Cooperative Study Group of Cancer Chemotherapy. Fourteen cases were evaluable and 3 of these showed partial response, giving a response rate of 21.4%. Toxic manifestations were experienced in fifteen of 18 cases (83.3%). Gastrointestinal toxicity was major and severe, especially diarrhea, which impeded the continuation of administration. This study revealed the usefulness of TK-117 for gastric cancer, but also the necessity of overcoming its toxicity, especially gastrointestinal complications.

Alteration in blood coagulation and fibrinolysis were observed serially after TAE 37 times by measuring PT, APTT, FDP, fibrinogen, AT III, plasminogen, and alpha 2-macroglobulin. Immediately after TAE, PT and APTT were prolonged, Fbg AT III, alpha 2-M, and platelets decreased, and FDP increased. These changes within 24 hours suggested that coagulation activities were accelerated, and fibrinolysis followed. Within four weeks after TAE, PT and APTT became most prolonged one to three days after, while AT III, Plg, and alpha 2-M became lowest on the third to seventh days. It is suggested that these decrease were mainly due to suppressed production resulting from damage of the residual liver.

The special feature of the arterial infusion method is that, when an anticancer agent is given, a high concentration of the drug is distributed through the nourish arterial system to the neoplasm. However, should the drug flow back to the heart and enter the second circulation system, the same dynamics hold as do in the venous route approach. Thus, using this feature, the suitable anticancer agent must be selected and the dose and regimen determined. Recently, continuous arterial infusion of 5-FU, MTX and other agents, arterial infusion of MMC and ADM over a given time course, plus microcapsulation of anticancer agents or improved chemotherapy for possible embolization, have been used to deal with embolisms. The most remarkable effects have been obtained in liver carcinoma among others. Rescue with antidotes to counter side effects of using the arterial route is relatively easy. There are agents suitable for arterial infusion among BRM, and favorable clinical applications are expected.

This report describes some aspects of tumor vessels and the functional characteristics of tumor microcirculation with regard to selective increase in tumor blood flow. Elevation of the mean arterial blood pressure to about 150mmHg by angiotensin II resulted in a several-fold increase in blood flow in tumor tissues without increasing blood flow in normal tissues. Pressure elevation by angio-tensin II also selectively increased tumor blood flow in intra-corneally transplanted microfoci and influx of lymph flow from the primary lesion to lymph node metastatic lesions. New techniques for analyzing microhemodynamics of tumor vessels showed that the vascular level in tumor tissues and the hydrostatic pressure difference between the tumor vessels and extravascular tissue were enhanced. Thus a new approach to cancer chemotherapy (ATII-induced hypertension chemotherapy) has been demonstrated in which the delivery to tumor tissue of systemically administered anticancer drugs can be selectively enhanced.

A multimodal treatment strategy for recurrent breast cancer is described. Occasionally, there are a few patients who have no other detectable distant metastases at the time of locoregional recurrence or of appearance of solitary lung metastasis. In such cases, curative results may be obtained with surgical treatment. In cases too extensive for surgical resection, irradiation is the treatment choice for local control. Radiotherapy is also helpful for painful bone lesions. The important basis for the multimodal approach to recurrent breast cancer is a well-balanced combination of local therapy with surgery or irradiation and systemic polychemoendocrine therapy or polychemotherapy followed by maintenance therapy, to improve the quality of life and survival of patients. Concerning the combined chemoendocrine therapy, many investigators have reported an improved effect with simultaneous or sequential use, but not all of these studies have confirmed the advantage of combination therapy over endocrine- or chemo-therapy alone, either in response rate or survival time. Further prospective randomized studies correlating ER status are needed to evaluate this approach. Immunotherapy used as a maintenance therapy may prolong the duration of remission and survival time.

The present status of endocrine therapy in the treatment of recurrent breast cancer was reviewed. Only one third of breast cancer responds to the endocrine therapy, and suitable patients should be selected the treatment. By means of estrogen receptor (ER), it is possible to select ER(-) patients who do not respond to therapy (response rate less than 10%) while 50-60% of ER(+) breast cancer patients respond to therapy. However, this is still unsatisfactory as 50-60% of recurrent breast cancer cases respond to combination chemotherapy. By adding to the ER status certain clinical parameters such as disease-free interval, metastatic site, and performance status, a better response would be obtained with endocrine therapy. The combination of chemotherapy with endocrine therapy would be expected to increase the probability of patient response. According to our prospective randomized trial, however, as well as other reported trials, the survival of patients treated with simultaneous chemo-endocrine therapy has not been prolonged as compared with those who had been treated sequentially with either therapy alone. This suggests that new therapeutic strategies will be necessary in the treatment of recurrent breast cancer.

Radiosensitization using Synkavit was first reported by Mitchell in 1953. Recently, renewed interest in radiosensitization has been shown by tumor radiobiologists since electron-affinitive hypoxic cell sensitizers were introduced Adams and his colleagues in 1973. Conferences on chemical modifiers i.e., radiosensitizers and radioprotectors, have been held every two years since 1977 in Britain or North America. At the last meeting in Banff, Canada in 1983 the results of randomized clinical trials of misonidazole were found to be rather disappointing and non-hypoxic cell sensitizers such as halogenated thymine analogues and PLD repair inhibitors were introduced. In parallel with these approaches, hyperthermia research combined with radiation was started in 1974. Very effective radiosensitization by heat-treatment, for example 43 degrees C for 40 min, has been shown in in vitro as well as in vivo experiments. Enhancement of the anti-tumor activity of some chemotherapy drugs using hypoxic cell sensitizers or PLD repair inhibitors was found to be a new approach for improving cancer chemotherapy in 1982. Hyperthermia was also shown to enhance the anti-tumor activity of some chemicals. Thus radiosensitization research may be extended to chemosensitization. i.e., from selective sensitization used in local radiotherapy to that used in systemic chemotherapy.

Sixty-seven patients with hematological malignancies and 4 with cancers were evaluated in this study. Standard administration of MCNU was instituted intravenously using 50-100 mg/m2 every 2 or 4 weeks, whereas some cases were treated with a higher dose therapy. Of 10 patients with chronic myelogenous leukemia, 7 achieved complete remission (CR), and 1 achieved partial remission (PR). A good response was also obtained in 9 of 10 patients with polycythemia vera and in all 4 patients with essential thrombocythemia. MCNU was less effective in malignant lymphoma (ML) and multiple myeloma (MM) than in myeloproliferative disorders. Two of 15 patients with ML and one of 21 patients with MM achieved CR, and two with ML and three MM achieved PR. Three patients with lung cancer and 1 with gastric cancer showed no response to MCNU. Delayed anemia, leukocytopenia and thrombocytopenia were observed in 38.7% of patients, and these were regarded as major side effects of MCNU. Nausea, vomiting, anorexia and elevated transaminase were also found in about 24% of patients, but only transiently. Our study indicates that MCNU is useful for chemotherapy of hematological malignancies, especially of myeloproliferative disorders. Therefore, further studies on combination chemotherapy with MCNU should be developed.