Progress of cancer chemotherapy has been mainly owed to the development of new antitumor drugs and the devices for enhancing the therapeutic effect of antitumor drugs. As for the enhancement of therapeutic effect, there are three major devices, that is, 1) a device to enhance the therapeutic effect by changing drug formulation, 2) enhancement of therapeutic effect by the combination of antitumor drugs with other treatment modalities and 3) enhancement by the combination with non-antitumor drugs. In this paper, major topics of these recent studies in Japan were reviewed. Especially, experimental studies on the enhancement of antitumor effect by the combination of antitumor drugs with calcium or calmodulin inhibitors and also overcome of vincristine resistance by the combination of vincristine with a calcium antagonist, verapamil, were described.

The history of adjuvant chemotherapy for gastric cancer in Japan was overviewed. As the most important trials of the early days, the trials of Imanaga Group (Cooperative Study Group supported by the grants from the Ministry of Health and Welfare) and of National Cancer Center Hospital were presented with final results. Furthermore, as the recent trials, the results of Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan (organized by Prof. K. Inokuchi) and of our study at Hiroshima University Hospital were presented. More than ten years has passed since the above early trials took place and the increase of five-year survival rate was clearly demonstrated in comparing the results obtained earlier days and current ones especially in stage III cases. This increase is attributed to the advances of cancer chemotherapy in the province of surgery.

Human tumor/nude mouse system is expected to be an antitumor screening system with higher predictability of the clinical effect. To establish this, it is quite necessary to fundamentally investigate the optimal treatment regimen in this new model, nevertheless few papers related to these subjects are currently, available. In this preliminary report, we examined the effect of several known antitumor agents against human breast tumor xenograft, MX-1, with reference to the dose, route and schedule of administration of drugs in comparison with the clinical regimens. As a result, the treatment regimens were desirable to be similar to that clinically done: the route of administration should be IV or PO, instead of IP often used in usual animal experiments. The selection of dose would be the most important factor, that is, the maximum tolerated doses (MTD) of mitomycin C, vincristine, etc. were higher than the clinical doses, even in terms of dose per square meter. Thus, for these drugs the risk to overestimate the effect might exist. On the other hand, the case was opposite as for 5-fluorouracil, because its MTD in the nude mouse was lower than the clinical dose. To evaluate the effect of a drug, it appeared to be reasonable to make account of not only the average percentage of tumor growth inhibition but also the statistical means such as Mann-Whitney's U-test.

Tumor cell killing effects of chemotherapeutic agents and hyperthermia are greatly enhanced in vivo as well as in vitro by the use of these two modalities in combination. The additive or synergistic effect is also observed in normal cells of the host animal. Therefore, the most important point of the strategy for clinical application resides in the selective damaging of tumor cells. From this point of view, several instructive reports which appeared recently were reviewed.

Continuous hepatic arterial infusion chemotherapy (HAI) and chemoembolization by microcapsulated Mitomycin C (MMC-m. c) were performed in patients with unresectable hepatoma or metastatic tumors of the liver. MMC-m. c showed significant antitumor effect and improvement of survival rate in unresectable hepatoma and liver metastasis of the breast cancer. Especially in liver metastasis of the breast cancer, MMC-m. c gained 80% of partial response rate and 11 months in 50% survival time. HAI was effective in multiple liver metastasis of colon and stomach cancer, showing 40% of one-year survival rate. A combination chemotherapy of HAI and MMC-m. c was performed in two cases of liver metastasis of the colon cancer. Tumor response was 100% in partial response rate. One of them died at 8 months and the other is alive at 8 months now.

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.

Since 1970, we have carried out cancer chemotherapy and immunotherapy in cooperation with Japanese scientists, particularly Prof. H. Umezawa, who has generously supplied bleomycin, peplomycin, acalcinomycin A (ACM), THP-adriamycin (THP), neothramycin and bestatin. Malignant tumors curable by pharmacotherapy are polycythemia vera (CR 100%), acute lymphoid leukemia (ALL) (CR 80%), Burkitt tumor (CR 80 or 50%), Hodgkin disease (CR 80%), chorioepithelioma (CR 80%), testicular cancer (CR 80%), ovary cancer of children (CR 80%), Wilms renal cancer (CR 60%), rhabdomyosarcoma (CR 75%), osteosarcoma (CR 60%), Ewing tumor (CR 60%), brain tumor of children (CR greater than 50%), testicular embryonal cancer of children (CR greater than 50%), acute myeloid leukemia (AML) (CR 50%), non-Hodgkin lymphoma (NHL) (CR 50%), ovary cancer of adults (CR 40%), small cell lung cancer (CR 20%) and breast cancer. Our experimental and/or clinical experience with ACM, THP, methoxy-9-ellipticine lactate, navelbine, 4-demethyl-epipodophyllotoxin-beta-d-ethyledene glucoside, bestatin and interferon is presented. ACM is effective against AML, ALL, NHL, Burkitt tumor, breast cancer. We have comparatively investigated cardiac and dermal toxicity of 12 kinds of anthracycline antibiotics and mitoxantrone, using golden hamsters. Of the drugs examined, ACM, THP, AD-32 and AD-143 cause much less cardiomyopathy and alopecia than the other agents. The results have been confirmed by electron microscopic studies. Bestatin is an immunorestorator, which recovers immunological functions decreased in aged animals. We hope that cancer chemotherapy and immunotherapy will progress in future and contribute to cure of neoplasms. Japanese scientists have been making a great contribution in the field of cancer pharmacotherapy, and we are eager to cooperate with Japanese scientists in cancer treatment studies.

Peplomycin containing combination chemotherapy with cyclophosphamide, hydroxy-daunomycin, oncovin and prednisone (CHOP-P) was performed in one patient with ATL and 8 patients with advanced diffuse lymphoma. CHOP-PM combination chemotherapy plus MTX was applied to 6 patients resistant to CHOP-P regimen. The overall complete remission rate was 53%, and 67% in non-T cell type and 50% in T cell type. However, only one patient out of 4 ATL patients showed complete response. Toxicities such as transient fever, myelotoxicities, G-I tract symptoms, hair loss and interstitial pneumonitis, were observed. Only in one out of 4 patients suspected drug-induced pneumonitis by peplomycin was observed. This regimen including peplomycin is considered to be one of the useful combination chemotherapies for diffuse lymphoma, especially non-T cell type and some of T cell type, except ATL.

A phase II study of KW2083 [7-N-(p-Hydroxyphenyl)-Mitomycin C], a derivative of Mitomycin C, was carried out in 20 patients with carcinoma of the lung and in 19 patients with metastatic pulmonary tumor. KW2083 was administered by single intravenous injection at a dose of 20-30 mg/m2 weekly or a single 70 mg/m2 dose. Patients treated with a dose of 20-30 mg/m2 should be given at least 3 doses for eligibility. Of 17 evaluable patients with carcinoma of the lung (11 adenocarcinomas, 3 squamous cell carcinomas, 2 small cell carcinomas and 1 large cell carcinoma), two patients with adenocarcinoma showed a partial response (11.8%). Two patients who achieved PR had adenocarcinoma without prior therapy received KW2083 at a single dose of 70 mg/m2 Objective response rates were 18.2% for 11 patients with adenocarcinoma and 25% for 8 patients with adenocarcinoma treated with a single dose of 70 mg/m2 of 15 evaluable patients with metastatic pulmonary tumor, no patients showed any objective responses. The hematologic toxicities were thrombocytopenia (less than 5 X 10(4)/mm3, 41.6%) and leukocytopenia (less than 2000/mm3, 28.1%); it was observed in 19% of the patients, that thrombocytopenia continued for more than 6 weeks after stopping therapy. Gastrointestinal symptoms such as anorexia (81%), nausea (66%) and vomiting (16%) were severe in patients treated with a single dose of 70 mg/m2. Fever in 19%, alopecia in 13%, phlebitis in 9%, eruption in 6%, stomatitis in 6% and liver insufficiency in 13% were also observed.

THP-ADM is a new antitumor antibiotic which belongs to the anthracycline group. This agent was administered to 42 histology proven various malignant disease patients with a schedule of 60-80 mg per body (40-55 mg per m2) iv bolus, every three weeks. THP-ADM administration revealed mild upper GI toxicity (vomiting 19%, stomatitis 21%) and leukopenia (less than 2,000 per mm3) in 80% and thrombocytopenia (less than 60,000 per mm3) in 38% with good rebound. There was no signs or symptoms of cardiac failure including the patient who had received 740 mg per body (500 mg per m2). Definite response (CR, PR) was observed in ovarian carcinoma 4/11, cervix carcinoma 2/7, breast carcinoma 1/6, malignant lymphoma 5/5 and mesothelioma 1/2. Furthermore, some response (MR) was observed in lung metastasis from endometrial carcinoma 2/4, and stomach carcinoma 1/3. The above indicated usefulness of this agent and further study should be continued, especially a controlled study with adriamycin.

Clinical study of HCFU for head and neck cancer was performed HCFU at a daily dose of 600 to 900 mg. Was orally administered to 30 patients, including 5 patients with metastases. The primary sites of cancer were: larynx 9 cases, mesopharynx 6 cases, hypopharynx 5 cases, maxilla 5 cases, nasopharynx 3 cases, parotid gland and floor of the mouth one each. All of them were squamous cell carcinoma except a case presenting parotid lesion caused by adenocarcinoma. In 7 cases receiving the single therapy of HCFU for one month, a positive response was presented in one out of 7. Twenty-three cases treated HCFU in combination with radiation, 11 showed complete response (CR: over 90% decrease of tumor size), 6 showed partial response (PR: over 50% decrease), 3 showed minor response (MR: over 25% decrease), and 3 were diagnosed as no change (NC). Positive responses evaluated as PR or above obtained at the mean cumulative dose of 25.7 Gy and HCFU 15972 mg. Four cases receiving HCFU in adjuvant chemotherapy were studied only for clinical toxicity. Clinical toxicities of HCFU in 30 patients were presented in transient pollakiuria (7 cases), neurotoxic effect (2), eruption and diarrhea (one each). Symptoms similar to anemia and unconsciousness caused by the intake of alcohol were found in 6 patients. Although positive effect of HCFU was observed only in one case being administered singly, it presented better results in more cases when administered in combination with radiation. The combination therapy also made the lesions respond faster than by radiation therapy only. Intake of any alcohol is not advisable.

Immunopotentiators may mitigate the depression of immunological function caused by the cancer itself or by chemotherapeutics. However, it has been found that these immunopotentiators reduce the metabolic activity of the host against drugs, including "masked" chemotherapeutics, which might be activated by metabolization in the body. Reported here is the result of serial experiments carried out on the activation of cyclophosphamide (CPM) in tumor-bearing animals, pretreated with phenobarbital, a drug-metabolizing enzyme inducer, and coenzyme Q10, a physiological activator of the electron transfer system in mitochondrias, in combination with immunopotentiators. Female Donryu rats (120 g body weight) implanted with Yoshida Sarcoma cells (YS) (2.5 X 10(6) i.p.) were treated with CPM (160 mg/kg X 1 i.p.), 84 hrs after implantation; the levels of the normustard-like substances (active metabolites of CPM) were serially measured. Some of the animals were also treated with PSK (125 mg/kg X 5 i.p.), a proteinpolysaccharide immunopotentiator obtained from mycelia of the Coriolus vesicolor, or with OK-432 (10 KE/kg X 5 i.m.), a streptococcal immunopotentiator. The results obtained were as follows: The blood levels of the normustard-like substances were lowered, i.e. the CPM activation was depressed in the YS-bearing rats and the depression was markedly intensified by PSK or OK-432 administration. Phenobarbital (40 mg/kg X 3 i.p.) or coenzyme Q10 (5 mg/rat X 5 i.p.) administration could mitigate the depression of the blood levels caused by the immunopotentiators, and the combination of phenobarbital with coenzyme Q10 could recover the blood levels up to those of the YS-bearing control rats, or even higher. YS-implanted (i.p.) rats treated with CPM+ immunopotentiators+coenzyme Q10 survived longer than those treated with CPM+immunopotentiators. These findings suggest the usefulness of coenzyme Q10 for the enhancement of cancer immunochemotherapy using masked compounds combined with immunopotentiators; all the more so, because coenzyme Q10 has also an immuno-stimulating effect, moreover, it presents almost no side effects in clinical application.

Effectiveness and side effects of VP 16-213, a semi-synthetic podophyllotoxin, on acute leukemia and histiocytic medullary reticulosis in childhood was tested. Four cases of refractory acute lymphocytic leukemia, five of acute non-lymphocytic leukemia-one induction failure and 4 in remission--and a case of histiocytic medullary reticulosis were treated with a combination of VP 16-213 (Days 1-5), cytosine arabinoside (Days 1-5) and adriamycin (Day 6). None of the acute lymphocytic leukemia patients yielded a complete response; however, one of them later attained a partial response with modified intermittent administration of VP 16-213 and cytosine arabinoside. A patient with acute non-lymphocytic leukemia who had failed to attain initial remission, achieved a complete response after the second course of the treatment with increased dosages. In the four acute non-lymphocytic leukemia patients in remission, complete remission was maintained more than 4 a months. A case of histiocytic medullary reticulosis demonstrated partial response. The major toxic effects produced by this regimen were marked pancytopenia and vomiting. VP 16-213 appears to be effective for myelocytic and monocytic malignancies in childhood.