Cancer chemotherapy is now the major modality to increase cure rate of cancer. In the past two decades systemic chemotherapy markedly improved the curability of several advanced malignancies in both adults and children. Several other cancers are also considered as curable by adjuvant setting. As for the low response group we must continue comprehensive approaches to improve response rate and duration. The knowledges of newer cancer biology provide us many ideas and targets of chemotherapy. The fundamental difficulties lie in cancer treatment are tumor side heterogeneity and host side individuality. Heterogeneity is now interpreted as the results of gene-instability and multi-oncogene involvement is of current interests. Thus in order to overcome these difficulties pharmacology-directed chemotherapy is now indispensable.

The relationship between the antitumor activity and the inhibition of thymidylate synthase after oral administration of 5-FU, FT-207 or UFT was examined. The inhibition of tumor growth on sarcoma-180 after oral administration of 5-FU (20 mg/kg), FT-207 (120 mg/kg) or UFT (30 mg/kg) was 40%, 50% or 70%, respectively. It was found that the inhibition of thymidylate synthase in sarcoma-180 tumor tissue after single oral administration of 5-FU (20 mg/kg), FT-207 (30 or 120 mg/kg) or UFT (30 mg/kg) were about 45%, 20%, 50% or 65%, respectively, but the activities of other enzymes involved in DNA synthesis were not almost inhibited. Thymidylate synthase was inhibited more severely by oral administration of UFT (30 mg/kg). The activities of other enzymes were not inhibited even by continuous oral administration of these drugs for 6 or 11 days. The extent of inhibition of thymidylate synthase seemed to be parallel to that of inhibition of tumor growth. These results suggest that the inhibition of thymidylate synthase by FdUMP converted from 5-FU, FT-207 or UFT plays a major role in their antitumor actions.

High dose ACNU and radiation therapy with autologous bone marrow rescue was performed in a 3-year-old boy suffering from cerebellar medulloblastoma, whose main mass had been removed at operation when widespread subarachnoid tumor dissemination was already present. The myelosuppression, which is a major side effect of high dose chemotherapy, was successfully prevented by the autologous bone marrow grafting and the serial CT scans showed complete disappearance of the tumor. However, the patient died on the 53rd day after the administration of ACNU of respiratory complication which was most likely due to pulmonary fibrosis. Although the autologous bone marrow rescue therapy is a technical advance to cope with myelosuppression secondary to chemotherapy, side effects of the other organs, particularly of the respiratory system, remain to be solved. The optimal treatment schedule should be established as soon as possible.

Certain chemotherapeutic agents against cancer have been used clinically as an immunosuppressive drug. In recent immunological advances it has been demonstrated that some chemotherapeutic agents can modify the antibody production and delayed-type hypersensitivity. In connection with modification of anticancer immune responses by the agents, many investigators have reported the increased production of NK cells in normal animals and of effector T cells in tumor-bearing animals, after administration of agents. Some authors have emphasized the possible role of the agent given before the tumor-inoculation for enhancement of host-mediated anti-tumor response on subsequent tumor growth. In general, these beneficial effects associated with the agents have been attributed to the abrogation of either suppressor T cells or macrophages. On the other hand, some reports including recent ones from this laboratory have described the production of tumoricidal macrophages by i.p. injection of the agent. The underlying mechanism (s), though not yet apparent, seems to be related to activation of macrophages. A small body of clinical suggests evidence suggesting immunoaugmentation by chemotherapy, but the therapeutic significance remains obscure. Though the immunoresponses , response components and the agents examined are heterogeneous and some results are restricted in a special experimental model, the immune response increase by anticancer chemotherapeutic agent in generally conceivable, and it should be further studied from the viewpoint of the host-mediated therapeutic effect.

Chemotactic response of macrophage to PHA was depressed at early stages in allogeneic sarcoma 180-bearing ICR mice and syngeneic X5563-bearing C3H/He mice and their depressed response were restored to the normal levels by PSK. Macrophages-dependent resistance against Listeria monocytogenes at early phase of infection was depressed at the early stage after tumor inoculation. The depressed resistance was restored by PSK in X5563-bearing mice and by a combination of tumor resection and PSK in sarcoma 180-bearing mice.

A phase I study of a new anthracycline, 4'-epiadriamycin was conducted in a total of 28 patients with various advanced cancers refractory to standard chemotherapies and 26 were evaluable. A dose limiting factor was leukopenia reaching a nadir approximately 2 weeks later and about one week needed for the recovery. Thrombocytopenia was milder and less frequent than leukopenia but dose-related. Nausea and alopecia were observed in the majority of patients but vomiting was relatively rare and therefore non-hematologic toxicities were judged to be milder than adriamycin. A recommended dose for patients having prior extensive chemotherapies was determined to be 60 mg/m2 in 3 weeks intervals.

The clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH X RH ethylamide (Leuprolide) against prostatic cancer was evaluated at the end of twelve weeks of administration of a daily dose of 20 mg subcutaneous injection to 22 patients with prostatic cancer. Of these 22 patients, 19 were previously non-treated and 3 had reactivated cancer. Complete regression was obtained in all patients with stage B or C cancer. Also, in 5 out of 12 previously non-treated patients with stage D cancer, Leuprolide administration proved to be effective for controlling prostatic cancer. However, Leuprolide therapy produced only stable effects at best in 3 patients who had reactivated cancer. It has no side effect and should be recommended as a drug of first choice in the treatment of previously non-treated prostatic cancer. It can be assumed from the present studies that the efficacy of this agent against prostatic cancer is mainly the result of its inhibitory effect on hypothalamo-pituitary testicular system, i.e., a medical castration effect.

A new method for the treatment of solid tumor, in particular, primary and metastatic liver cancer using a hydrophobic-polymer conjugated macromolecular anticancer agent, smancs is described. Smancs was dissolving in a lipid contrast medium, Lipiodol, as an injection into the feeding artery. The marked antitumor effect was observed in both experimental animals and human trials. In the patients with hepatocellular carcinoma, both reductions in tumor size and alpha-feto-protein were observed in 91% of the patients. The survival period of the treated patient with highly advanced stage and inoperable cases was comparable to or better than that of resected cases. No major side effect such as bone marrow suppression or liver toxicity was observed due to selective drug delivery to the tumor. About half of the patients, however, showed a transitory fever (37-39 degrees C) for 1-3 days. The mechanism for such selective tumor targeting of anticancer agent appears to be due to the difference in the vascularity of tumor and normal tissue. Furthermore, we found that lack of lymphatic clearance system in the tumor made the prolonged and selective retention of such lipophilic drug in the tumor tissue possible. Another advantages of this method are found in radiological approaches. Differential diagnosis of primary or metastatic cancer became possible and dosing regimen can be determined since a presence of the contrast medium is restricted to the tumor area and it parallels to that of the drug being dissolved. Insufficiency in X-ray staining indicates a need for subsequent injection. The selective remaining of Lipiodol in the tumor for long period may help follow-up study as well.

Biological effect of bestatin against rat ascites hepatomas was investigated. Bestatin administration inhibited effectively growth of AH 130, AH 44 and AH 66, and prolonged survival days of the tumor-bearing rats. In addition bestatin slightly exhibited interferon production in spleen cells from ddY mice in vitro.

Biological effect of bestatin in combination with bleomycin against rat ascites hepatoma AH 66 was investigated. The combined use of bestatin and bleomycin both at a dose of 0.5 mg/kg was found to have a strong inhibition of the tumor growth. The combined effect was also confirmed histologically as follows. In combination group, increase of necrobiosis area in the tumor lesion, augmentation of infiltration of lymphocytes and macrophages around the solid tumors, and marked replacement of necrotic area by fibrous granular lesion were stronger and more rapidly than that in the other group.

A number of reports of regional intraarterial infusion chemotherapy for malignant tumors have been published. Balloon occluded arterial infusion was newly developed by us. Balloon catheter is used for temporal occlusion of the hepatic artery during intraarterial infusion of anticancer drugs. Interruption of the arterial blood flow keeps the drugs at high concentration for a long time in the distal artery to the occluded portion. This procedure has been performed in 87 cases of hepatomas and metastatic liver cancers with the sufficiently good results.

A draft of guideline for phase III study of anticancer drugs was presented, and its objective problems in practical aspect was discussed. The anticipated of phase III study is to evaluate the clinical usefulness of anticancer drug in terms of effectiveness and toxicity. And the comparative study of new drugs with standard therapy is most important. The comparative study includes two trials: randomized controlled trial and the second non-randomized controlled trial. Considering the precision of study, the randomized controlled trial is most rational, but it includes some controversies in practical use and ethical aspect. On the other hand, non-randomized controlled trial includes some problems on comparability in relation to prognostic factors.

The main purpose of the phase I clinical study is to define the tolerable doses in each various administration schedules depend upon by careful clinical observations and by pharmaco-kinetic, -dynamic studies. final goal of the phase I clinical study is to establish the safe, most reasonable administration schedules to perform further clinical studies, including phase II, III and possibly iv. In addition, it is quite reasonable to observe efficacy of the given agent if possible. The patients who are selected to receive the phase I clinical study should be fulfilled the followings: (1) Histological proof of malignancy; (2) No best available therapy regimen at present; (3) Maintain reasonably well organ functions which are suitable to observe side reactions (4) No hang-over reactions from previous therapy and; (5) Consent from patient himself or members of the family concerning the study. The set-up of the initial administration dose should be established from mouse and dog preclinical studies. Retrospective studies revealed reasonably safe and efficient to start from the most sensitive dose in 1/5 LD10 of mouse or 1/5 TDL of dog on the mg square meter basis. Above method is widely used at present and it is a potential replacement for the large animal species as a routine procedure. Dose escalation routinely proceeded using a double dose escalation procedure or modified Fibonacci procedures with minimal risk. It is permitted to escalate administration dose in the same patient under careful considerations. The new agent which has enough reliable clinical date in the abroad, the clinical study in this country would be simplified. The phase I clinical study should be performed in the well-equipped institutions under the supervision of capable investigators. The guide line of phase I clinical study would be revised whenever it is necessary.

One of the major causes of failure in cancer chemotherapy is the selection and proliferation of specific drug-resistant tumor cells during treatment. The mechanism of acquired resistance of tumor cells to some agents is related to intracellular drug accumulation and retention. For example, in vincristine (VCR)- and adriamycin (ADM)-resistant tumor cell sublines, these agents can be shown to enter the cell but are actively transported to the outside. This results in a relatively low intracellular level of drug and thus to low cytotoxicity. These observations suggest that if we could control the VCR- and ADM-efflux function of resistant tumor cells appropriately, then we could expect a reversal of acquired resistance to these drugs in drug resistant tumor cells. We found that calcium channel blockers and calmodulin inhibitors enhance the intracellular level of vincristine and adriamycin in tumor cells, especially in drug-resistant mouse and human tumor cells by inhibiting their outward transport. The approach using calcium modifiers has the following advantages. (1) Reversal of acquired resistance to vinca alkaloids and anthracyclic antibiotics can be attained. Calcium channel blockers, such as verapamil, diltiazem, nicardipine, niludipine and nimodipine, at doses of 30 to 125 mg/kg administered daily for 10 days with VCR (10-200 micrograms/mg) enhanced the chemotherapeutic effect of VCB (40-50% increase in life span) in P388/VCR-bearing mice. The calcium channel blockers also enhanced the therapeutic effect of ADM in ADM resistant P388 bearing mice. (2) The approach is also effective for the reversal of the inherent resistance of tumor cells to anticancer agents. Less sensitive tumor cells became more susceptible to VCR and the heterogeneity in drug sensitivity among tumor clones has been circumvented. (3) The approach with these calcium modifiers is also effective against other antitumor agents which are transported outside the cells by the similar mechanisms. As one of the mechanisms of cross-resistance is explained by the enhanced drug efflux from resistant tumor cells, antitumor agents which show cross-resistance to VCR and ADM become effective against resistant tumor cells by this approach. The mechanism of this approach is now under investigation. These calcium modifiers enhance the cellular level of antitumor agents by inhibiting their outward transport. The functions of cellular calcium and calmodulin in the membrane architecture and membrane functions might be involved in this process. Clinical evaluation is now under progress by using diltiazen, nicardipine and verapamil.