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.

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.

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.

Experimental models of meningeal gliomatosis (MG) have been produced by intracisternal inoculation of C6 and 9L glioma cells into Wistar and Fisher 344 rats, respectively. Chemotherapy of these models and in vitro chemosensitivity assay for these cell lines were studied with ACNU, BCNU and VM-26. In vitro chemosensitivity assay revealed that 9L cells were sensitive to all of the anticancer drugs above, and that C6 cells were resistant to ACNU and BCNU, but not to VM-26. In vivo experiment, the survival time of the rats inoculated with 9L glioma cells (9LMG) was prolonged by both ACNU and BCNU but not by VM-26. None of these drugs were effective against the rats inoculated with C6 glioma cells (C6MG). It is concluded that the result of in vitro chemosensitivity assay is not always correlative with that of in vivo. This implies that an in vivo chemosensitivity assay system including MG models is indispensable in researching into chemotherapy of brain tumor.

Estracyt is a new drug for treatment of prostatic cancer, which is a molecule combining estradiol and nornitrogen mustard by a carbamate link. Estracyt is completely dephosphorylated prior to reaching the peripheral circulation after oral administration of the drug to men. Estramustine, i. e. dephosphorylated Estracyt, appears to be metabolized in liver as follows: Estramustine leads to estromustine leads to nitrogen mustard + estrone. There is a large amount of estramustine binding protein (EMBP) in the cytosol 3.5 S fraction of human prostatic cancer tissue, which is involved with the selective uptake and long term retention of both estramustine and estromustine in prostate. The anticancer action of Estracyt appears to be the sum of the direct prostatic action of estramustine and estromustine and the indirect prostatic action of free estradiol-17 beta and estrone via the inhibition of hypothalamo-pituitary axis. Estracyt Research Group in Japan concluded that Estracyt was effective in 38% of reactivated prostatic cancer patients (15% (I-C, I-B), 23% (I-A, O-B, O-C]. Side effects of this drug at the time of 3 months treatment is as follows: gastrointestinal disturbance in 36%, edema in 15%, and hepatic disorder in 7%.

For the analysis of the mechanism of cancer metastasis, effects of anticancer agents on the NK activity of spleen cells and on the artificial metastasis of B-16 melanoma cells were comparatively studied. The inhibitory effect of these anticancer agents on the growth of B-16 melanoma inoculated to foot pad of C57/BL6 mice was also examined. The growth of B-16 melanoma was inhibited by intravenous administration of 6 mg/kg of MMC, 18 mg/kg of KW-2083 and 5 mg/kg of CDDP, but not of 6 mg/kg of KW-2083. The NK activities in spleen cells of C57/BL6 mice administered with 6 mg/kg of MMC and 18 mg/kg of KW-2083 were decreased, but they were not decreased in mice administered with 6 mg/kg of KW 2083 and 5 mg/kg of CDDP. Significant increases in the number of artificial pulmonary and liver metastasis were observed in mice administered with 6 mg/kg of MMC and 18 mg/kg of KW-2083. It is suggested that the depression of NK activity induced by anticancer agents results in the promotion of metastatic disease.

Clinical study of UFT which was a mixture of FT and uracil, was conducted on 16 patients with urogenital malignancies. Seven patients had renal cell carcinoma, 5 patients had bladder cancer and 4 patients had prostatic cancer. UFT was continuously administrated at doses of 300 mg or 600 mg per day. One of the patients with renal cell carcinoma and 1 of the patients with bladder cancer showed a complete response, and 1 patient with each cancer showed a partial response, but none of the 4 patients with prostatic cancer responded. In total, complete or partial responses were obtained in 4 of the 16 patients, given an effective rate of 25.0%. Concerning side effects, 3 of the 16 patients complained of anorexia, nausea and vomiting, and stomatitis, but no hepatic or renal disorders, or marrow depression was observed.

To evaluate the time response of anticancer drugs, we observed the morphological changes of solid tumor cells using a new simple method of cytologic examination. Mitomycin C and Bleomycin were administered to nude mice transplanted with human uterine cervical carcinoma of the Yumoto strain. The cancer cells were classified as follows: A, uniform, pyknotic nuclei with indistinct nucleoli; B, pyknotic nucleus with distinct nucleoli; C, pale-stained nuclei and cytoplasm; D, condensation of nuclei and cytoplasm. Three hours after MMC administration the destruction of the nuclei of A type cancer cells and shrinkage of B type cells was observed. Pyknosis of B type cells and destruction of C type cells was seen 7 hours after BLM administration. These characteristic changes which occurred at a very early period appear to be available as a marker for the evaluation of the oncostatic effect and for the anticancer drug selection in patients with malignancy.

The antiemetic effect of domperidone against nausea, vomiting, and anorexia induced by antineoplastic agents was compared with that of chlorpromazine. Twenty patients with malignant neoplasms given 2 cycles of a combination chemotherapy including cisplatinum and adriamycin received domperidone in one cycle and chlorpromazine in another cycle. Antiemetics 10-20 mg were given 30 minutes before chemotherapy and every 4-6 hours afterwards by div, iv, or po. No significant differences in severity of nausea and vomiting and duration of anorexia were noted between domperidone and chlorpromazine. Side effects were observed in 11 patients who received chlorpromazine, while none was observed in domperidone. It was concluded that domperidone was as effective as chlorpromazine as antiemetics and more useful because of its lower incidence of side effects. The antiemetic effect of domperidone, however, was not great enough for some patients, especially when they received cisplatinum. A higher dose of domperidone or domperidone with concomitant use of glucocorticoids should be considered as promising antiemetics for these patients.