CPT-11 is a new derivative of Camptothecin. Phase I clinical study of single administration with CPT-11 was carried out by a cooperative study group. Starting from 50 mg/m2 (n), dose was escalated to 350 mg/m2 (7n). Dose limiting factor was found to be a decrease in WBC counts (especially in neutrophils), and MTD was presumed to be 250 mg/m2 or more. Nadir of WBC counts was observed after about a week, and it took 2-3 weeks for recovery. The decrease in platelet number and hemoglobin content was mild. Other side effects included G-I toxicities, alopecia, etc. However, no toxic effects on the heart, kidney, lung were observed. SN-38, main metabolite of CPT-11, was observed in blood, and excreted rapidly. Anticancer effects were suggested with dose of 165 mg/m2 or more against colon cancer, gastric sarcoma, melanoma and lung cancer. It is suggested that the optimal dose schedule for an early Phase II study is 200 mg/m2 every 3-4 weeks. However, not only leukopenia but also marked G-I toxicities being noted in some cases, care should be taken for those side effects.

The 6-day subrenal capsule assay for determining chemotherapeutic sensitivities of brain tumors was studied. Rat glioma 9L and ACNU resistant 9L-2 were transplanted under the renal capsule of normal immunocompetent WKA rats for laboratory investigation. Evaluation of implanted tumor growth till 12 days was performed. The effects of chemotherapeutic agents administered intravenously were evaluated by measuring the growth rate of implanted tumor specimens. The results obtained from SRC were compared with the results from colony forming assay. Both were correlated to each other. On the other hand, histological investigation revealed that implanted human tumor cells had been diminished and implanted tumor was replaced by immunoreactive cells from the host in many cases. These results threw doubt on a reliability of SRC. To avoid this immunoreaction, cyclophosphamide was injected as immunosuppressive agent subcutaneously 24 hours before implantation. In such cases, the growth rates of implanted tumors were increased and histologically the implanted tumor cells existed for 6 days after implantation. Twenty-three malignant brain tumors (malignant astrocytomas 16, metastatic tumors 5, malignant lymphoma 2) were obtained as surgical specimens. Evaluable assay rate of our study were 89%. 15 patients with malignant astrocytomas were studied about correlation between the sensitivities of ACNU and post-operative clinical courses. Overall clinical correlation of 15 cases of malignant astrocytomas was 47%. These results from subrenal capsule assay are not seemed to be beneficial for clinical use. Immunoreactive response when using immunocompetent rats must be solved in future.

The therapeutic evaluation of rG.CSF has been studied on neutropenic patients receiving lung cancer chemotherapy with focusing the change in the absolute neutrophil counting (ANC) in the patients during chemotherapy and subsequent rG.CSF treatment by daily dosing either at 0.4, 2.0, 5.0 and 10.0 micrograms/kg intravenously or at 2.0 and 5.0 micrograms/kg subcutaneously. The daily rG.CSF dosing for 14 consecutive days was performed on the patients upon completion of the 28-day chemotherapy for lung cancer. As a result, remarkable recovery of ANC was observed in the patients administered at doses of more than 5 and 2.0 micrograms/kg intravenously and subcutaneously, respectively. Additionally, the shortening of the neutropenia (ANC: below 1,000/cmm) was observed in the patients at doses of not less than 2.0 micrograms/kg in both administration routes. In conclusion, rG.CSF treatment demonstrates the completion and/or shortening of the chemotherapy cycle for lung cancer at a subcutaneous dose of 2.0 micrograms/kg and at a intravenous dose of 5.0 micrograms/kg. No adverse drug effects were observed in all patients during the study.

A subrenal capsule assay (SRCA) was performed on 34 fresh surgical specimens from 31 urinary transitional cell carcinoma (TCC) patients. On day 6, 97.7% of explants were detected macroscopically and tumor cells were present in 45.6% of all explants microscopically. In control groups, there was a negative correlation between the change in explant size (delta TS) and the percentage of the area of interstitial tissue. And in the several explants on day 6, the pseudocysts made up of cancer cells were seen. These support that urinary TCCs from fresh surgical specimens grow under the renal capsule. An evaluable assay rate of 97% was given. Susceptibility to cisplatin (CDDP), adriamycin (ADM), methotrexate and cyclophosphamide (CPM) was seen in 33%, 41%, 32% and 29%, respectively, of tumors using the delta TS method. In interstitial tissue rich tumors, a higher rate of susceptibility to anticancer drugs was given using the delta TS method than using the tumor growth inhibition rate (TGIR) method. There was a positive correlation between the rate of S-phase cells of the tumor and the susceptibility using the delta TS method. But, there was no correlation between this and the susceptibility using the TGIR method. These findings suggest that the delta TS method is more practical than the TGIR method. In addition, the growth of explants was better in immunosuppressed mice with 180 mg/kg of CPM than in normal mice. And the effectiveness of a combination of CDDP and ADM was seen as an anti-tumor effect or a reduction of side effects.

One of the major problems with cancer chemotherapy is the development of drug resistance during treatment. Two mechanisms are considered as the cause of drug resistance, natural and acquired. It is now considered that cancers can be composed of multiple clonal subpopulations of cancer cells. In this study, we separated three clones (C1, C3 and C8) from NBT-2 (human bladder cancer cell line) by limiting dilution. We examined the growth rate and the transplantability to nude mice and performed chromosomal analysis of three clones. The doubling time of C1 is 22 hours, and those of C3 and C8 were 25 and 36 hours, respectively. Each clone was transplantable to nude mice, but we could not find out any histological difference among them. The chromosome numbers of C1 was 66, and those of C3 and C8 were 68 and 63, respectively. We could also find out karyotypic difference among them. We could therefore consider that these three clones had different biological features and studied the difference in drug sensitivity among these three clones and the parent cell line. Cells (1 x 10(4)/well) were incubated in microplates with ten different chemotherapeutic agents for 72 hours. Then 3H-thymidine (1 microCi/ml) was added to each. After 24 hours, cells were harvested and the uptake of 3H thymidine was counted with a liquid scintillation counter. According to the reaction pattern, these chemotherapeutic agents were divided into three groups. 1. The radio isotope uptake of three clones and parent cell line was proportionally inhibited by increasing the drug concentration (carboplatin, (glycolato-o, o-) diammine platinum (II), ifosfamide).(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a 11-year-old boy with NHL, who developed interstitial pneumonitis following high-dose MCNU with autologous peripheral stem cell transfusion. Non-productive cough, malaise and progressive dyspnea on exertion were noticed 7 weeks after high-dose MCNU (600 mg/kg) treatment, and chest X-ray revealed a bibasilar reticular pattern. Arterial blood was hypoxemic and pulmonary function showed the development of a restrictive ventilatory effect and a reduced diffusing capacity for carbon monoxide (DLCO). Clinical Symptoms were resolved after 3 courses of m-PSL pulse therapy and 6 months prednisolone, but an isolated reduction in DLCO has been present. This case suggests that pulmonary toxicity is a dose limiting factor for MCNU treatment.

HCFU was orally administered to 14 patients with hepatocellular-carcinoma, (including 11 patients with liver cirrhosis) and evaluated of HCFU and 5 fluorouracil (5-FU) levels. Blood and tissue 6-8 hr. after oral administration. The concentration of 5-FU in tissue was almost in the effective levels. In addition, the 5-FU level in the tissue of hepatocellular carcinoma tended to be higher than in non cancerous portion of the liver. 5-FU tissue concentration was not correlated with various laboratory data for the liver function (K-ICG, T. bil, GOT, GPT, etc.) From these results, it is suggested that HCFU is a useful anticancer agent for hepatocellular carcinoma especially for the cases accompanied liver cirrhosis.

Proliferation and differentiation of the normal endometrium are orderly regulated by female sex steroid hormones. In this connection, development and growth of endometrial cancer have also thought to be controlled in part by sex steroid hormones. Furthermore, some of the sex steroid hormones, progesterone, for example, are used as therapeutic agents in the management of endometrial cancer. The role of estrogen as a promotion factor of endometrial cancer is understood by unopposed estrogen hypothesis, and relative excess of estrogen unopposed by gestagen is regarded as an important factor for the development of endometrial cancer. High dose administration of gestagen has been used as a therapeutic agent of endometrial cancer over these three decades, and now the oral administration of medroxyprogesterone acetate (MPA) is mainstay, with response rate of approximately 30%. However, recently some cases with serious side effect, mainly thrombosis, have been reported. These cases should be regarded as a grave warning to easy usage of MPA. Therefore, the search for more effective and safe way for clinical application have to be requested; for example, clarification of the precise mechanism of anti-tumor effect of MPA on endometrial cancer or development of new hormonal therapeutic agents. Moreover, basic research in the field of cancer and hormone may create a new era in cancer therapy in the future.

The effect of various anticancer drugs on alpha-fetoprotein (AFP) secretion and some other properties of human hepatoma cells was investigated in vitro with the following results. (1) There was a high correlation between AFP secretion and cell number after treatment of human hepatoma cells with anticancer drugs and the amounts of AFP secreted per 10(4) cells per 72 hours (AFP-secreting capacity) were not affected within therapeutically achievable concentrations (TAC). (2) The AFP-secreting capacity was affected with some exceptions in the cells treated with higher concentration of drugs than TAC. Furthermore, chromosomal and morphological aberrations in the similarly treated cells, were also observed, suggesting the relationship between the change of AFP-producing capacity and that of some other properties.

In order to clarify the cause of arterial changes after intra-arterial infusion of anti-cancer drugs (AI-AD) experiments were made on the arteries of rabbits. Histopathologic sections, 7 days after AI-AD revealed endothelial damage characterized by pyknosis, hyalinization with edematous change of the intimal layer. Proliferation of the endothelial cells was also observed. The cause of narrowing or occlusion of the arteries was considered to occur with thrombus formation surrounded by the proliferated endothelial cells and this suggested that thrombolytic agents would be effective to prevent these arterial changes.

Human monocytic colony-stimulating factor (hM-CSF) is a glycoprotein which stimulates monocyte production in the bone marrow. It enhances CSF (such as G- and GM-CSF) production of monocytes and megakaryocyte-potentiating activity (Meg-POT). It also enhances tumor-killing activity of monocytes against several leukemic cell lines such as K562, U937, HL60 and Daudi. In the clinical studies, it was shown that hM-CSF infusions accelerated the recovery from neutropenia as well as thrombopenia after anticancer chemotherapy against hematological, gynecologic and urogenital malignancies. Human M-CSF infusions were tolerable without any serious side effects. It is reported that infusions of G-CSF and GM-CSF cause the increment of leukemic cell counts in some cases, but hM-CSF infusions did not increase leukemic cell counts. These results indicate that hM-CSF may be potentially useful for the treatment of myelosuppression induced by cancer chemotherapy in cancer patients.

DNA damaging agents such as nitrosoureas are widely used for the treatment of malignant gliomas. Therefore, quantitative measurement of DNA damages induced by antineoplastic drugs is useful to judge the efficacy of the drug and understand the pharmacological action of the drug. We have utilized in situ nick translation method to demonstrate "nicks" in DNA of glioma cells treated by various antineoplastic agents. Exponentially growing rat 9 L glioma cells (4 x 10(4] were seeded in the chamber slide. After fourty eight hours, the medium was changed to that containing various concentration of the drug (ACNU, cis-DDP, BLM, ADM and VP-16) and the cell was treated for 1 hour. Then, the cell was fixed for 10 minutes in methanol-acetic acid (v/v 3:1). Following fixation, the cell was incubated in the nick translation mixture containing E. coli DNA polymerase I, 3H-TTP, and 4 dNTP's (ATP, GTP, CTP, CTP and TTP) for 10 minutes at room temperature. The slide was dipped in the autoradiographic emulsion, exposed for 4 days at 4 degrees C, and then developed, the number of the silver grains over nuclei was counted under the microscope. For comparison of the effect of the drug to glioma cells, IC50 (inhibitory concentration of the drug for 50% cell kill) of each drug was determined by treating the cell for 48 hours at the various concentration of the drug. Small number of the silver grains was noted in cells with no treatment. Over IC50 as the concentration of the drug increased, the number of the nick increased in cells treated with bleomycin or adriamycin which are known to produce single strand breaks in DNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Muramyl dipeptide (MDP) and its synthetic derivatives which comes from the major constituent of bacterial cell wall has various biological activities as host defence mechanisms. One of the synthetic MDP derivatives, MDP-Lys (L 18), muroctasin has potent biological activities with less adverse reactions among various MDP derivatives. Muroctasin has proved to be safe to use clinically as the results of phase I clinical study. We attempted to evaluate its clinical usefulness and safety from the view point of restorative activity in leukopenia that was induced by cancer chemotherapy in patients with malignancies. It is concluded that muroctasin is effective as well as useful on the restorative activities against leukopenia in lung cancer patients after cancer chemotherapy, with the optimal daily dosage of 200 micrograms for six times by subcutaneous injections through phase II and phase III clinical cooperative studies in Japan. Supposed mode of action of muroctasin for granulocytosis may be the results of CSF production due to stimulation of macrophage by muroctasin. This first clinical success of restoration of leukopenia in patients with cancer receiving cancer chemotherapy by MDP derivative, muroctasin, might be not only advantageous for cancer chemotherapy and/or radiation therapy but also for preventing infections occurring in compromised host due to neutropenia in cancer patients by means of cytotoxic cancer chemotherapy or irradication.

Sixteen patients with malignant glioma were treated by the intravenous administration of beta-interferon together with chemoradiotherapy. Five of the cases were recurrent gliomas. Seven of the 11 fresh cases were treated with beta-interferon, more than two months after cessation of the radiotherapy. Of the 16 cases, 12 cases showed partial regression of tumors, or no regrowth of tumors on CT scan, 2 cases showed no improvement, and 2 cases were unevaluable due to the short follow-up periods. IFN-beta is often administered, in combination with antineoplastic agents and radiotherapy, to patients with malignant glioma. Some patients have shown sufficient suppression of the growth of the malignant glioma only through administration of IFN-beta 1 x 10(6) IU once or twice a week. Some patients, however, have developed severe bone marrow suppression due to the combination therapy of IFN-beta and antineoplastic agents. Therefore, the blood of patients should be tested twice a week, and the data should be analyzed within the same day to determine the subsequent treatment. IFN-beta administration should be stopped if the platelet count drops below 1.0 x 10(5)/mm3 or half of the initial figure, and the course of disease of the patient should be carefully observed.

Twenty lines of human gastro intestinal and breast cancer xenografts, in which chemosensitivity spectra by the in vivo nude mouse assay had been clarified. were subjected to the in vitro SDI (succinate dehydrogenase inhibition) assay using MTT dye to assess the accuracy of this drug sensitivity test against 4 drugs i.e., mitomycin C (MMC), adriamycin (ADM) 5 fluorouracil (5-FU), and cisplatin (CDDP). After 3 days incubation, the suspension of every tumor cells including small fragments showed a marked decrease of SD activity even when no anticancer drug was added to the assay medium. Among these 4 drugs evaluated MMC exhibited a statistically significant correlation between chemosensitivity values of the in vitro SDI assay and those of the nude mouse assay. However, the other 3 drugs demonstrated no correlation between the values of these two methods. Since the primary cultured fibroblasts revealed, in general, lower sensitivity to these drugs, contamination of fibroblast may decrease the SDI values when materials from solid tumors with rich stroma such as a type of stomach cancer were subjected. It is considered that the prediction of chemosensitivity to every drug will be impossible by a in vitro SDI assay.

The achievement of complete response in cancer chemotherapy is most important for prolongation of survival period and improvement of quality in patient's life. Because of the above, chemosensitivity-oriented chemotherapy is required. Human tumor clonogenic assay (HTCA) and subrenal capsule assay (SRCA) provide relatively precise in vitro and in vivo methods for determining the chemosensitivity of individual cancer patients. The success rates are 52% in HTCA and 77% in SRCA. HTCA has an initiative for an evaluation using fluid samples and SRCA can be used against lymphomas and sarcomas which show low success rates in HTCA. Until now both methods show high predictivity of drug response in clinical situation and especially high true positive rate in SRCA is striking.

Lipiodol, an oily contrast medium, is utilized to deliver the anticancer agent SMANCS to the target tumor in which the tumor selective delivery of 2,500 fold more than plasma was confirmed with prolonged retention in the tumor tissue. This unique tumor targeting is accomplished by the arterial injection of the oily formulation of the drug. The method utilizes unique vascular properties of tumor tissue. SMANCS is a derivative of neocarzinostatin conjugated with copolymer of styrene and maleic acid. It has much propronounced lipophilicity, stability against various harsh environments and exerts a potent cytotoxicity. Therapeutic effect of the drug to unresectable primary hepatoma is much better than the conventional method. For Child A category patients with intrahepatic metastasis in no more than three area, a 3 yr survival rate is more than 87%. When the Child's A and B are combined with no distant metastasis, 1-, 2- and 3-year survival rates are 87%, 50%, and 35%, respectively. The side effect of this treatment [SMANCS/Lipiodol, i.p.] is minimal; transitory low grade fever is the commonest one (40-50% of cases) which can be controlled by a routine protocol. No liver or marrow toxicity was observed. Procedural limitations for the lung cancer etc. are discussed.

The antitumor activities of five anticancer drugs, at IC50 dosages cisplatin (CDDP), adriamycin (ADM), etoposide (VP-16), mitomycin C (MMC) and carboplatin (CBDCA) were studies an 7,12-dimethylbenz (a) anthracene induced rat ovarian cancer cell line (DMBA-OC-1) and a human ovarian serous adenocarcinoma cell line (KOC-1S). The IC50 dosage of anticancer drugs for DMBA-OC-1 was: CDDP 0.2 microgram/ml. ADM 0.04 microgram/ml, VP-16 3.0 microgram/ml, MMC 0.1 microgram/ml and CBDCA 10.0 micrograms/ml. The results of our study except those for MMC were parallel with those published on in vivo studies. The IC50 dosages of DMBA-OC-1 did not have enough antitumor activity for KOC-1S, whereas the original KOC-1S tumor strongly resisted the combination chemotherapy (CDDP, ADM and cyclophosphamide). Therefore, our findings suggested the possibility of the separation of multiple drug resistant clones from KOC-1S. These two cell lines had quite different antitumor activity characteristics.