[Clinical evaluation of 2-mg granisetron tablet for nausea and vomiting induced by anticancer drugs including cisplatin].

The antiemetic effects on nausea and vomiting induced by anticancer drugs and safety of a 2-mg granisetron tablet were studied in cancer patients, particularly in the field of gynecology, who had been treated with anticancer drugs including cisplatin (CDDP) at 50 mg/m2 or more. The 1-mg granisetron tablet is already commercially available and used widely in clinical practice by oral administration of two tablets per dosage. In this investigation, the clinical efficacy, safety and usefulness of a 2-mg tablet, which can be taken more easily, were studied. The 2-mg granisetron tablet was judged to be "remarkably effective" or "effective" for nausea and vomiting in 22 (66.7%) of 33 patients. For safety, neither adverse experiences nor abnormal laboratory values were judged to be of clinical significance. The 2-mg granisetron tablet was considered "extremely useful" or "useful" in 22 (66.7%) of 33 patients. The above results confirmed the excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and the high degree of safety of a 2-mg granisetron tablet.

Expression and intracellular localization of heat shock proteins in multidrug resistance of a cisplatin resistant human ovarian cancer cell line.

TYK-R10 is a cisplatin resistant human ovarian carcinoma cell line and showed a cross resistance to various anti-cancer drugs including adriamycin (ADR), vincristine (VCR) and etoposide, despite a lack of multidrug phenotype. Under normal conditions, various heat shock proteins (HSPs) were expressed in TYK-R10 but not in parental line (TYK-nu). Non-lethal short-term heat shock treatment induced a high tolerance for cisplatin and VCR in TYK-R10 and ADR, and VCR in TYK-nu. This treatment induced and/or enhanced the expression of various types of HSPs in various intracellular localizations in both TYK-R10 and TYK-nu, with minor differences. These findings indicate that combined expression and intracellular localization of HSPs may play an important role in drug resistance of TYK-R10.

[Is routine second-look operation justified for stage I ovarian cancer?].

The results and role of second-look operation (SLO) were evaluated in 33 patients with stage I epithelial ovarian cancer. 1. At SLO, histological evidence of disease was not identified in any of 24 patients, but washing cytology showed class III in 2 patients. 2. Only one (4.5%) patient with stage Ic (washing cytology: positive) has had a recurrence following negative SLO. 3. Recurrent tumor developed in 2 (33.3%) of the stage Ic (capsular invasion) patients and 1 (16.7%) of the stage Ic (washing cytology: positive) patient, but all patients with stage Ia or Ic (surgically ruptured by surgeon) are alive without recurrence. 4. Based on this experience, our current recommendation for patients with stage Ia or Ic (surgically ruptured by surgeon) epithelial ovarian cancer following comprehensive staging surgery and primary chemotherapy is that they do not require routine SLO.

A clinicopathologic study of 30 patients with Paget's disease of the vulva.

Clinical and pathologic analyses were performed in 30 patients with Paget's disease of the vulva to investigate the risk factors for recurrence. From 1971 to 1993, we carried out histologic examinations in 27 resected vulvae to detect Paget's cells at the surgical margin. Prior to 1981, 9 patients underwent the examination, and 6 of them had positive surgical margins, and 2 of these 6 patients had local recurrence. After 1982, the preoperative multiple biopsy and intraoperative frozen section diagnosis of the surgical margins were performed, and as a result, cases of the lesions remaining as stumps on the vaginal side decreased in 7 of 18 examined patients. In these 7 cases, 2 cases had local recurrence. The patients were further divided into three groups according to histologic findings to investigate their prognosis: 10 patients with intraepithelial Paget's disease (IEP), 9 patients with minimally invasive Paget's disease (MIP), and 11 patients with underlying carcinoma (UC) including 2 cases of carcinoma in situ. Four locally recurrent cases were found in IEP or MIP, and the longest period from surgery to recurrence was 8 years and 4 months. The invasive UC lesions persisted or recurred shortly after surgery (median, 10 months) and 5 of the 6 patients with general metastasis. For IEP and MIP, surgical margins of the vaginal side should be carefully examined with preoperative multiple biopsy and intraoperative frozen section, and also a long-term follow-up is necessary. With regard to invasive UC patients, their prognosis was found to be very poor for general metastasis.

Choriocarcinoma in a term placenta with pulmonary metastasis.

This is a case report of choriocarcinoma in the placenta of a patient who had a term delivery at the 38th week of pregnancy. The pregnant woman had hemoptysis at the 26th week of pregnancy, and a chest X-ray revealed a tumor in the left lung. She had suffered from a hydatidiform mole in a previous pregnancy in 1989. The patient's serum level of beta-human chorionic gonadotropin (hCG) had been below the normal level before the present pregnancy. Choriocarcinoma was histologically found at 3 sites in the placenta. Her urine hCG levels decreased rapidly after delivery. A partial lobectomy was performed after 2 courses of chemotherapy, and no choriocarcinoma was recognized histologically, because the lesions were hemorrhagic and necrotic. At present, the mother is free of disease, and the baby is growing normally. The placenta should be examined in a detail in post-molar pregnancy.

[Clinical evaluation of granisetron injection against nausea and vomiting induced by anticancer drugs including cisplatin].

The antiemetic effect and safety of granisetron injection on nausea and vomiting induced by anticancer drugs were studied in the patients treated with anticancer drugs including 50 mg/m2 or more of cisplatin (CDDP). Granisetron is already on the market, and drip infusion of granisetron at 40 micrograms/kg has been used widely in clinical practice. In this clinical investigation, a simpler administration method of its slow (30 to 60 seconds) intravenous injection at 40 micrograms/kg just before CDDP administration was used. The clinical efficacy, safety and usefulness against nausea and vomiting were investigated in 22 patients, and the study medication was assessed as "remarkably effective" or "effective" in 16 patients (72.7%). Neither adverse experience nor abnormal laboratory test value was reported. In the usefulness rating, the study medication was assessed as "extremely useful" or "useful" in 16 out of 22 patients (72.7%). The above results have shown that the slow intravenous injection of granisetron has an excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and a high degree of safety.

[Pharmacokinetics of carboplatin in a patient under hemodialysis].

A patient with ovarian cancer under long-term hemodialysis was treated with carboplatin at 240 mg/m2 via intravenous drip infusion for 30 min. Hemodialysis was performed 1 or 2 hrs after the administration of carboplatin. The pharmacokinetics of carboplatin were determined, plasma total and free carboplatin-derived platinum (total Pt and free Pt) levels declined rapidly in the former. The AUC, T1/2 and Cmax of total and free Pt were estimated to be 7.14 and 3.14 mg/ml x min, 35.1 and 18.2 h, and 15.1 and 10.0 micrograms/ml, respectively. Plasma total and free Pt levels showed the same as normal control in the latter. The AUC, T1/2 and Cmax of total and free Pt were estimated to be 8.70 and 5.09 mg/ml x min, 27.6 and 21.9 h, and 13.2 and 13.2 micrograms/ml, respectively. No severe side effect was observed after administration of carboplatin. In conclusion, carboplatin may be given to the patient 2 hrs before hemodialysis in view of the pharmacokinetics.

[Effects of various growth factors on the proliferation and the differentiation of trophoblastic cells in vitro].

EGF, PDGF, IL-6, TGF-beta 1 and supernatants from decidual cell cultures were added in various concentrations to cultures of normal trophoblastic cells in vitro. Effects on cell proliferation and differentiation were assessed by using 3H-thymidine uptake test and measuring hPL, hCG production in culture media, respectively. EGF stimulated only hPL, hCG production and in contrast, PDGF stimulated 3H-thymidine uptake only. IL-6, TGF-beta 1 and decidual supernatants stimulated both hPL, hCG production and 3H-thymidine uptake, especially TGF-beta 1 and decidual supernatants. These results suggest that EGF is related to the differentiation, PDGF is to the proliferation, and IL-6, TGF-beta 1 and decidual supernatants are to both the differentiation and proliferation of trophoblastic cells. Further understanding of the effects of these products on trophoblastic growth may provide important insights into mechanisms of early pregnancy development.

Establishment and characterization of a subline predisposed to pulmonary metastasis from a human gestational choriocarcinoma cell line in nude mice.

A subline predisposed to pulmonary metastasis was successfully derived by repeating in vivo selection of GCH-1, a human gestational choriocarcinoma cell line, in nude mice. While the parent line GCH-1, transplanted subcutaneously to nude mice, induced pulmonary metastasis in a few of the host animals, the newly established subline GCH-1(m) successfully metastasized to the lungs in 100% of them. Compared with GCH-1, GCH-1(m) exhibited a higher degree of cell atypia, a lower capacity for cell growth and markedly higher productivity for human chorionic gonadotropin (hCG). Another characteristic of this subline was its enhanced growth after the addition of a pulmonary extract obtained from nude mice. The relationship of these findings to the mechanisms of metastasis of this cancer was discussed.

[Isolation of cisplatin-resistant subline from human ovarian cancer cell line and analysis of its cell-biological characteristics].

The cisplatin (CDDP)-resistant subline TYK-nu (R) was developed by culturing TYK-nu (human ovarian cancer cell line in vitro) with exposure to CDDP in stepwise increasing concentrations. The characteristics of both cell lines were compared and the results were as follows; 1. Both cell lines formed a monolayer in a pavement-like arrangement and large cells were occasionally present in TYK-nu (R) rather than TYK-nu. The population doubling time of TYK-nu and TYK-nu (R) was 43 hr and 48 hr, respectively. 2. IC50 (microgram/ml) in 96 hr treatment with CDDP and carboplatin (CBDCA) was 0.035 and 0.5 in TYK-nu and 0.62 and 2.0 in TYK-nu (R), respectively. 3. In the intracellular CDDP concentration, there was no marked difference between TYK-nu and TYK-nu (R) after CDDP (2.0 micrograms/ml) treatment in 2hr. 4. After treatment with CDDP (0.2 microgram/ml) or CBDCA (2.0 micrograms/ml), a decrease in S and G2 + M compartments was observed in the pattern of the DNA histogram of TYK-nu, but not in that of TYK-nu (R). 5. The majority of chromosomes in both cell lines were in hyperdiploid areas and the mode of TYK-nu and TYK-nu (R) was 56 and 51, respectively. The karyotype of TYK-nu (R) showed deletion of chromosome 7q. Thus, compared to TYK-nu, TYK-nu (R) was 17.7 times more resistant to CDDP and 4 times more resistant to CBDCA. The results suggest that the mechanism of resistance to CDDP may be due to genetic changes at the cellular level.

[Antitumor effect of UFT on human ovarian cancer grafted to nude mice and 5-FU concentration in tumor and normal tissues].

Antitumor effects of UFT, tegafur (FT-207), cisplatin (CDDP) and the combination of UFT with CDDP on a human ovarian cancer xenograft in nude mice and the concentration of 5-FU in the tumor tissue and major organs were studied. UFT (48.6mg/kg/day X 20) or tegafur (15.0mg/kg/day X 20) was daily administrated orally, and CDDP (5mg/kg/day X 3) was administrated intraperitoneally at an 7-day interval. The inhibition rates of the tumor growths were 49.6% with UFT, -2.3% with tegafur and 17.7% with CDDP, respectively. In the combination of UFT with CDDP, severe side effect were observed. The concentration of 5-FU in UFT-treated group was higher than tegafur group: about 2 times in the tumor, 5 times in the liver, 9 times in the kidney and 4 times in the spleen, respectively. In the combination of UFT with CDDP, the concentration of 5-FU in major organs, especially in the kidney, in nude mice that died at 10 day after drug administration were higher than in those of UFT. These findings indicate that UFT increases the intratumoral concentration of 5-FU to elicit better antitumor effect and also the concentration of 5-FU in various normal organs after long time administration.

Expression of HLA-DR molecules in human gestational choriocarcinoma cell lines and malignant cell lines.

In order to determine whether trophoblast (or gestational choriocarcinoma) expresses the HLA-DR antigen or not, it was analysed using human gestational choriocarcinoma cell lines (GCH-1, GCH-1(m) and TAK-N) by the Northern hybridization method. TYK-nu (human undifferentiated ovarian carcinoma cell line), M-14 (human malignant melanoma cell line), L-14 (human B lymphocyte cell line), and KKNS-1, KKNS-2 and KKNS-3 (three human endometrial carcinoma cell lines) were also examined. Messenger ribonucleic acids (mRNAs) were prepared from 2 X 10(7) cells in each cell line and hybridized by HLA-DR alpha-chain complementary deoxyribonucleic acid (cDNA) probe (pDR alpha-1) and beta-chain cDNA probe (DK-10). Northern hybridization analysis revealed that GCH-1 transcribed at least two kinds of alpha-chain (16s and 23s) and beta-chain mRNA (15s and 23s). TYK-nu transcribed alpha- and beta-chain mRNA, L-14 transcribed only alpha-chain mRNA, and TAK-N appeared to transcribe only a little alpha-chain mRNA. The HLA-DR molecules were not, however, expressed in the other cell lines (GCH-1(m), M-14, KKNS-1, -2 and -3). These results are compared with those obtained by immunocytochemical methods in our laboratory.

[Establishment and characterization of two histologically differentiated human uterine endometrial carcinoma cell lines from the same patient--a correlation between grade of morphological differentiation and HLA antigens].

The cell lines designated KKNS-I and KKNS-II were derived from the metastatic lesions in the lymph nodes of endometrial adenocarcinoma. The KKNS-I cells were small spindle or polygonal in shape and showed a jig-saw puzzle-like arrangement with a tendency to pile up. The KKNS-II cells were polygonal in shape, and larger than the KKNS-I. They appeared to be arranged like a pavement. The modal number of the two cell lines was 46 without marker chromosome. Calculating from the growth curves, the doubling times for the KKNS-I and the KKNS-II cells were 35 hours and 60 hours, respectively. The tumors obtained from the nude mouse inoculated with the KKNS-I and the KKNS-II were a poorly differentiated endometrial adenocarcinoma and a well differentiated endometrial adenocarcinoma in histology, respectively. The volume of estrogen receptor and progesterone receptor in the KKNS-II were more than that in the KKNS-I cells. HLA-ABC antigens were detected in both the cells, but HLA-DR antigens were detected in only some populations of KKNS-II cells. These data suggest a relationship between the HLA-DR antigens and the degree of differentiation of the endometrial adenocarcinoma.

[Anti-tumor and adverse effect of etoposide and cisplatin on human choriocarcinoma transplanted to nude mice--a correlation between effect and tissue distribution of the drugs].

The study dealt with anti-tumor and adverse effects of etoposide and cisplatin on human choriocarcinoma cell line (GCH-1) transplantable in nude mice in relation to the rate of their uptake into tumor tissue. Nude mice were divided into 3 groups (etoposide, cisplatin and MTX-group), 7 to 9 per group and received drug treatment which started when their tumor grew to 100 approximately 300 mm3 in volume. All drugs were intraperitoneally administrated to nude mice (each drug: 1/4 mouse LD50 dose X3, weekly). The inhibiting action on the tumor was observed to be etoposide greater than cisplatin greater than MTX. The body weight loss of nude mice was observed to at its maximum in the cisplatin-treated group. The serum beta-HCG level did not rise in the drug-treated groups but rose in the non-treated control group. No histopathological changes characteristic of each drug were found. A concentration of etoposide and cisplatin in various tissues was serially measured after one shot intraperitoneal injection of etoposide 25 mg/kg or cisplatin 5 mg/kg. Etoposide reached its peak concentration after 30 minutes in tumor, liver and kidney and, after 4 hours, was left with 37.1%, 10.4% and 2.3% concentrations after 30 minutes in tumor, liver and kidney, respectively. Cisplatin showed similar kinetics, but was found to remain at a comparatively high concentration in both liver and kidney. Thus, it was demonstrated that etoposide and cisplatin were active against the human choriocarcinoma cell line. Furthermore, the less adverse effect of etoposide was felt to be partially due to its lower residue in liver and kidney.

[Establishment of a cell line from human ovarian cancer (undifferentiated carcinoma of FIGO classification) and analysis of its cell-biological characteristics and sensitivity to anticancer drugs].

A new ovarian cancer cell line has been established from the dispersed cells taken from a heterotransplanted tumor at the 6th passage in nude mice which had been serially transplanted with a primary lesion of undifferentiated carcinoma (FIGO) of the ovary. Selection of cancerous epithelioid cells was completed by the 4th passage by means of the colonial cloning method. The cell line designated TYK-nu was subcultured serially in Eagle's MEM with 10% FCS more than 100 times over 31 months at March, 1986 and was observed to produce a tumor on implantation into nude mice histologically similar to the original tumor. These cells form a monolayer in a pavement-like arrangement with polygonal cells including giant cells and reveal a lack of contact inhibition. PAS positive substance can be seen in the cytoplasm. Desmosome structure, well-developed cell organelles and glycogen granules can be found by electron microscopy. The population doubling time was about 37 hours and the plating efficiency was 13-17%. All cells were seen to be of the human karyotype on chromosomal analysis and the number of chromosome in the majority of cells was hyperdiploidy with a mode of 56 at the 6th and 84th passages. A submetacentric marker chromosome was present. Using in vitro colony assay, TYK-nu was studied for drug sensitivity to cisplatin, adriamycin, vincristine, 5-fluorouracil and etoposide, and found to be sensitive to cisplatin.