Biomedical subjects

H Majima

Publications and source records attributed to H Majima.

At least 19 recordsLinked to original sources

PubMed1995

Phase I study of NKT-01.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

Adult↗

PubMed1995

Further application and evaluation of critical cell number and modifying factors in radiocurability of multicellular spheroids.

Relationship of cure and surviving clonogenic cell number after various doses of X-irradiation was examined in multicellular spheroids of LCT1 human lung adenocarcinoma cells, LCT2 human lung small cell carcinoma cells and FSA1233 mouse fibrosarcoma cells. Some of these spheroids were cured at such doses that considerable number of clonogenic cells still survived after irradiation. Radiocurability was analyzed by comparing total clonogenic cell number in spheroids, cellular radiosensitivity and critical cell number Nc, i.e., the minimum number of clonogenic cells required to produce regrowth. (Nc-1) cells were killed by post-radiation processes and the larger the critical cell number, the more radiocurable. The LCT2 spheroids had the largest critical cell number and were most radiocurable. To investigate underlying mechanisms, modifying effect of heavily irradiated (HIR) tumor cells on the clonogenicity, i.e., plating efficiency of unirradiated tumor cells was investigated. Plating efficiencies with HIR cells showed significant decrease in LCT2 cells, no change in LCT1 cells and increase in FSA1233 cells. The results indicated that in case of LCT2 spheroids some of viable cells surrounded by dying or dead cells might have been killed with unknown toxic effect additional to direct irradiation effect. Thus, critical cell number analysis may be useful to quantify and to compare modifying effect of cellular/environmental factors in curing process of spheroids or tumors.

Adenocarcinoma↗

PubMed1992

Radiation and thermal sensitivities of murine tumor (FSa-II) cells recurrent after a heavy irradiation.

Radiation and thermal sensitivities, and cell doubling times (Tds) of C3Hf/Sed mouse FSa-II cells recurring after a heavy irradiation were examined in vitro. Tumors in the leg were irradiated with gamma-rays and observed for late recurrence (in vivo clones), or removed immediately after irradiation and single cell suspensions were plated for colony formation (in vitro clones). Five subclones were selected from original cells in vitro. Survival curves were fitted to the multi-target and linear quadratic models. Surviving fractions at 2 (SF2) and 10 Gy (SF10) irradiations, and those at 30 and 60 min heatings at 44 degrees C (SF30 and SF60), were obtained for each clone. Although, Tds of subclones were slightly longer than those of the parental cells, those of recurrent clones were prolonged substantially with an exception of one cell line. Radiosensitivities of FSa-II parental cells tested in vitro and in vivo were equally radioresistant. Thermal sensitivities of parental cells tested in vitro and in vivo were also identical. All subclones were more radiosensitive compared to the parental cells. The in vitro recurrent clones showed smaller D0 (radiation dose to reduce survival from S to S/e in the exponential portion of survival curve) than the D0 of the parental cells. The SF2 values of four in vitro recurrent clones were greater than that of the parental cells whereas those of two lines were smaller. It was of interest that the in vivo recurrent tumor cells showed a wide variation in the radiation sensitivity. Among 9 tumor cell lines examined, 4 lines were more sensitive and 4 were more resistant compared to the original. FSa-II subclones as well as both in vitro and in vivo recurrent clones showed a wide variation in thermal sensitivity. No consistent changes in the shoulder or in the slope were found. The SF30 or SF60 showed that 5 out of 9 in vivo recurrent clones and 4 out of 9 in vitro clones were more resistant compared to the original cells. No correlation was observed between thermal and radiation sensitivities. The Td was not related with radiation or thermal sensitivity.

Adaptation, Physiological↗

PubMed1992

Linear quadratic model of radiocurability on multicellular spheroids of human lung adenocarcinoma LCT1 and mouse fibrosarcoma FSA.

The LCT1 cells derived from a human lung adenocarcinoma and the FSA cells from a mouse fibrosarcoma were found to form spheroids. The cure-dose relationship of spheroids and the survival curves of their component cells were analysed by using a linear-quadratic model for cell survival and a Poisson distribution for cure. The analysis resulted in three conclusions: (1) the double minus logarithm of cure probability was linearly related to radiation dose, (2) the critical cell number was constant at any given cure probability, and (3) cellular radiosensitivity was also constant. The experiments seem to meet these conditions for each of two kinds of spheroids. Control doses (50%) were 20 Gy for LCT1 spheroids and 21 Gy for FSA spheroids, both 400 microns in diameter. The analysis showed that the lower cellular radiosensitivity and the higher number of clonogenic cells made LCT1 spheroids more radioresistant than FSA spheroids and that the higher critical number of 130 cells made the LCT1 spheroids more sensitive than the FSA spheroids with 18 such cells. The overall radiocurability of spheroids was a result of these three opposing effects, indicating that the critical cell number can be one important factor in determining the radiocurability of multicellular systems.

Adenocarcinoma↗

PubMed1992

[A phase I study of DWA2114R].

Phase I study of DWA2114R, a new platinum analogue, was conducted in 39 patients with various tumor types by a group of 13 institutions. Of the 39 patients entered in this study, 35 were evaluable. The starting dose was 40 mg/m2 (1N) and the drug was administered i.v. for 20-30 min, escalating stepwisely up to 1,000 mg/m2 (25 N). The dose limiting factor (DLF) was leukocytopenia, especially neutrocytopenia, and the maximum tolerated dose (MTD) was more than 1,000 mg/m2. Major clinical toxicity was gastrointestinal. Hepatotoxicity and nephrotoxicity were mild. Following administration of the drug, plasma concentrations of total and filterable platinum (Pt) showed a triphasic and biphasic decays. Excretion into urine within 24 hours was in the range of 54.2% to 92.2% of the administered platinum. The recommended dose of phase II study was 800-1,000 mg/m2, repeating every 3-4 weeks.

Adult↗

PubMed1992

[Phase I study of a new platinum complex 254-S, cis-diammine (glycolato)-platinum (II)].

A new platinum complex 254-S had a superior preclinical therapeutic indices compared to cisplatin, showing decreased renal and gastrointestinal toxicities. Phase I clinical study with a single dose schedule was conducted to investigate the safety, toxicity, pharmacokinetics and possible efficacy against various advanced cancers by a cooperative study of 10 institutions. The drug was administered by i.v. infusion for 60 min dissolved in 250 ml of 5% xylitol solution, without the use of hydration and antiemetics. At least 3 patients at each dose level of 10, 20, 40, 80, 100 and 120 mg/m2 were tested and 28 patients were entered into this study. Myelosuppression, especially thrombocytopenia, appeared strongly at dose level of 80 mg/m2 and dose limiting thrombocytopenia was found in 2 of 5 patients. Leukocytopenia was also dose-related but moderate. Platelet and WBC nadirs occurred around 3 weeks after administration with recovery in about one week. Although slight elevation of BUN and creatinine were temporarily observed in a few cases, no significant renal toxicity was observed. Anorexia, nausea and vomiting were observed in the majority of patients, but milder than cisplatin. In conclusion, 254-S has demonstrated reduced non-hematologic toxicities as compared to cisplatin. This drug appears to be well tolerated and 120 mg/m2 was maximum tolerated dose. The recommended dose for phase II studies was thought to be 100 mg/m2 by i.v. infusion every 4 weeks.

Adult↗

PubMed1992

[A phase II study of DWA2114R, a new platinum complex for breast cancer].

A multi-institutional phase II study of DWA2114R was conducted in breast cancer. DWA2114R at doses of 800-1,000 mg/m2 was administered by 1-hour intravenous infusion every 3-4 weeks on minimal two cycles. Fifty-two patients entered the study; 34 were eligible, 7 ineligible. Eleven patients were dropped from evaluation due to incomplete observations. There were 1CR, 6PR, 1MR, 12 NC, and 14 PD with an overall response rate of 20.6%. A median duration of responses was 11 weeks. Leukopenia and nausea/vomiting were frequently observed but well tolerated and recovery was quick. It is concluded that DWA2114R is a useful drug in the treatment of breast cancer.

Anorexia↗

PubMed1991

A case of calcifying carcinoma of the stomach with long-term postoperative survival.

A 28 year old man suffering from calcifying carcinoma of the stomach underwent a gastrectomy which was histologically classified as being a noncurative resection. As postoperative adjuvant chemotherapy, he received 116 mg of Mitomycin C and 454.8 g of Tegafur as well as 5690 g of ascorbic acid. He showed carcinoma cells histologically at both oral and anal edges of the resected specimen, and peritoneal metastases of tumor cells were also observed, but he nevertheless kept a performance status of 1 until 5 years after surgery. The patient finally died of cachexia 5 years and 6 months after his operation. Among 42 patients with calcifying carcinoma of the stomach reported in the foreign literature and 19 patients reported in Japanese, those patients for whom the postoperative survival time was clearly indicated did not necessarily survive longer than those patients without calcification.

Adult↗

PubMed1991

Cell shedding from x-irradiated multicellular spheroids of human lung carcinomas.

We studied the effect of radiation on cell shedding from the surface of multicellular spheroids. Spheroids were produced from two human lung cell lines, one adenocarcinoma (LCT1) and the other small cell carcinoma (LCT2), by using a liquid overlay culture technique. The number of cells shed from both kinds of spheroids did not change significantly when they were irradiated. The number of clonogenic cells shed from both kinds of irradiated spheroids decreased sharply as the dose of irradiation increases. There were no significant differences in clonogenic cell shedding per spheroid between LCT1 and LCT2 spheroids. 400 microns spheroids were more radioresistant to inhibition of clonogenic cell shedding than 250 microns spheroids. Shed cells were more radiosensitive than spheroid cells. In these experiments, we did not obtain any results indicating that radiation enhances metastasis.

Adenocarcinoma↗

PubMed1991

[Pharmacokinetics of KRN 8602 in cancer patients].

The pharmacokinetic properties of KRN 8602, an anthracycline compound, was studied by HPLC following intravenous administration of KRN 8602 to cancer patients. The results were as follows. (1) The plasma concentration-time curve declined as a triphasic function (alpha, beta, gamma) (t1/2 (alpha) = 0.02910, +/- 0.0054 hr, t1/2 (beta) = 0.704 +/- 0.319 hr, t1/2 (gamma) 8.37 +/- 1.37 hr). The blood cell concentration was higher than that in plasma. (2) The distribution volumes of the tissue compartment were larger than those of the central compartment. This result suggested that KRN 8602 would be easily transferred into the tissues. (3) The area under the curve (AUC) of KRN 8602 increased in proportion to the increase of dosage. (4) The metabolites of KRN 8602 were detected in plasma, blood cell and urine. (5) Urinary excretion of KRN 8602 and its metabolites were extremely low.

Adult↗

PubMed1991

[Phase I study of CI-898. CI-898 Study Group].

We conducted a phase I study of CI-898 (trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).

Adult↗

PubMed1991

[Phase I clinical study of antineoplastic agents].

Routinely, phase I clinical study starts with 1/10 of MELD10, provided dog does not produce toxicity. This is empirical method depend upon previous agents. In these days, many new agents appear to clinical study and some of them require so many steps to reach MTD. This is mainly depends upon differences of ADME between animals and human, which is possible to eliminate by pharmacokinetic studies. On the other hand, some of agents exceed MTD with initial dose of 1/10 MECL10. This is mainly due to difference of target organ sensitivity, and could be eliminated by assay of tissue enzyme activities. Another point should be emphasized is the existence of plasma peak level toxicity. This should be eliminated to perform preclinical study of LD10 by continuous infusion rather than iv bolus injection. Since some of new agents have DLF of neuro, hepato or cardiac toxicity rather than bone marrow, those would show quite different behaviors, therefore a special attention should be given for further studies.

Antineoplastic Agents↗

PubMed1991

[Evaluation of cardiotoxicity in new anthracycline analog ME 2303. ME 2303 Study Group].

ME 2303 is a new anthracycline analog which differs from adriamycin in the sugar moiety. ME 2303 displays a higher antitumor activity against L 1210 and P 388 Leukemia than adriamycin. To evaluate the cardiotoxicity of ME 2303, ECG tracings (21 patients) and Holter ECGs (9 patients) were recorded before and after the administration of ME 2303 for various malignancies (mean dose 123.8 mg/m2), and some of the electrocardiographic parameters were analyzed. Control ECGs were normal in 17 patients, in 4 patients minor ECG findings like sinus tachycardia (2 patients), low voltage (1 patient) and flattening of the T wave (1 patient) were observed. After treatment, no relevant ECG changes were observed except one case who showed a flat T in pretreatment ECG. In this patient developed ST-T changes were seen after treatment. The basic rhythm was sinus rhythm in all of the cases, and the heart rate showed no significant changes. ME 2303 had no effects on the specialized conduction system. With regard to arrhythmia, no increase in number and severity was observed. In Holter ECG no development of ST-T changes was seen after treatment.

Adult↗

PubMed1990

[Multi-drug chemotherapy for patients with peritonitis carcinomatosa associated with ascites].

Between 1973 and 1987, 257 patients with ascites were seen in our divisions and 101 deaths due to cancer out of those who received multi-drug anticancer chemotherapy were surveyed: 1) They consisted of 45 ovarian cancers, 15 uterine corpus cancers, 5 uterine cervical cancers and 36 unknown primary cancers, or cancers other than gynecologic malignancies. 2) Survival time from the time of aspiration of ascites tended to be longer in four years from 1977 and 1981 than in four years from 1973. 3) The survival time was different in each patient groups having various combination chemotherapy and the longest was seen in the group of patients who received THP-ADM and CDDP-containing regimen as the next. 4) Patients survived for the longest period when a total amount of ascites less than 100 ml was aspirated and patients whose ascites was drained out more than 50,000 ml were the next longest survivors. 5) Clinical efficacy by multi-drug chemotherapy for malignant ascites was possibly predicted by our drug sensitivity assay by using primary cultured cancer cells.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Presurgical evaluation for dental implants using a reformatting program of computed tomography: maxilla/mandible shape pattern analysis (MSPA).

A new analysis technique that provides a shape pattern of the maxilla or mandible is described. This technique uses a software program of computed tomography multiplanar reformation (CT/MPR). The successive cross-sectional images obtained by the CT/MPR are numbered, and the height and width of the maxilla and mandible at each of these cross-sectional images at specified levels are measured. The measured height and width are plotted against the number of the cross-section. This technique, termed maxilla/mandible shape pattern analysis (MSPA), creates an easy profile of the shape of the maxilla and mandible, and it enhances treatment planning for the placement of dental implants.

Aged↗

PubMed1990

[A markedly effective combination therapy of 5'-DFUR and MMC in advanced gastric cancer--a case report].

We performed a combination therapy with two drugs, 5'-DFUR and MMC, which proved to be markedly effective in one patient. The patient was 73-year-old female with tumor, advanced cancer gastric lower third portion. Borrmann type 3, an poorly differentiated adenocarcinoma. Since the patient rejected an operation, the drug therapy was selected. Oral administration of 5'-DFUR 800 mg daily was combined with intermittent intravenous administration of mitomycin C. In 3 years, the cancerous site got scarred and no distant metastasis was observed. Presently, she feels well, receiving an outpatient treatment.

Adenocarcinoma↗

PubMed1990

[Thermal radiosensitization in vitro and its implication to radiotherapy].

Thermal radiosensitization and the possible mechanism are reviewed. In vitro studies suggest that hyperthermia can enhance cell killing by radiation resulting in a steeper slope and smaller shoulder of the cell survival curve, compared to the survival were following radiation clone. Molecular studies suggest that inhibition of DNA synthesis and or repair of DNA damage by hyperthermia might be major causes of the thermal radiosensitization. When the curve is fitted by linar quadratic (L-Q) model, a increased number of beta, while relatively stable amount of alpha values are shown for survival curve to radiation combined with hyperthermia. This implies that when a larger radiation dose (greater than or equal to 4 Gy) is combined with hyperthermia, the enhancement would be greater in thermal radiotherapy.

Cell Survival↗

PubMed1990

[Phase I clinical study of MX2 (KRN 8602)].

KRN 8602 is a new antineoplastic drug with the chemical structure, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. This drug was developed in an attempt to improve the clinical efficacy of currently used anthracyclines. In preclinical studies, KRN 8602 has been shown to produce less cardiotoxicity and alopecia, yet has comparable antitumor effects to adriamycin. In addition, KRN 8602 has shown antitumor effects on adriamycin-resistant tumors. A phase I clinical study was undertaken to determine the toxicity of KRN 8602 given as a single i.v. dose. Toxicity evaluation included CBC with differentials, platelet counts, SMA chemistry profile, EKG, urinalysis, plain chest X-ray and physical examination. Myelosuppression was the major side effect noted with leukopenia, and especially neutropenia, being dose-limiting. The degree of WBC suppression was dose-related and MTD appears to be 30 mg/m2. Nausea and vomiting were observed in cases who had received more than 10 mg/m2. No patient had alopecia. No obvious cardiotoxicity in this study. Maximum total cumulative dose of KRN 8602 was 450 mg/m2. Further observation is necessary to confirm this point. In this study of 10 cases, one breast carcinoma with bilateral lung metastasis revealed definite regression of metastasis for more than 18 months with this agent alone. This patient had previous chemo- and hormone therapy, containing adriamycin. The above preliminary phase I clinical study suggests strongly the usefulness of KRN 8602, and further investigations are indicated.

Adult↗