Yoshihito Furuhashi

Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases

Twenty‐nine ovarian cancer patients with yolk sac tumors and germ cell tumors with yolk sac tissue as a component of their disease (16 endodermal sinus tumor, 11 mixed germ cell tumors, one embryonal carcinoma, and one polyembryoma) were treated with cytoreductive surgery and combination chemotherapy. Prognostic factors were investigated in this group. Patients with Stage I disease had a more favorable prognosis (P < 0.003) than those with Stages II and IV disease. The difference in prognosis was significant in cases where residual tumor was absent (P < 0.003) and in cases where ascites was either absent or less than 100 ml in volume (P < 0.05). Endodermal sinus tumor with either an intestinal (P < 0.05) or microcystic pattern (P < 0.01) was more common in survivors than in those who died. The age, preoperative serum alpha‐fetoprotein level, maximum tumor size, and tumor weight had no significant correlation with prognosis. In advanced cases, chemotherapy regimens including cisplatin gave better results than those containing vincristine, dactinomycin, and cyclophosphamide (P < 0.05). The optimal treatment of yolk sac tumors or tumors with yolk sac tissue as a component of the ovary is discussed in light of these results.

α-Fetoprotein in malignant germ cell tumors of the ovary

To investigate the clinical significance of alpha-Fetoprotein (AFP) in malignant germ cell tumors of the ovary, we studied 46 patients who were treated by the Tokai Ovarian Tumor Study Group. The 46 patients had the following tumors: immature teratoma (IT), 17 cases; endodermal sinus tumor (EST), 16 cases; mixed germ cell tumor containing EST, 11 cases; embryonal carcinoma, 1 case; polyembryoma, 1 case. In all 29 non-IT cases, AFP was positive, and in 27 cases (93%) the level was above 1000 ng/ml. In 11 of 17 cases of IT (64.7%), AFP levels were elevated and in 1 case the level was above 1000 ng/ml. Elevation of the AFP level above 1000 ng/ml suggested the presence of EST. AFP levels were monitored in 27 of 29 cases without IT during treatment and follow-up. It was found that AFP levels should be monitored closely for at least 1 year after induction of remission. No recurrence was observed when AFP continued to be negative longer than 1 year. The mean interval to clinical recurrence from the reelevation of AFP was 4 months (1.4-9 months). An increase in the AFP to a positive level, even without clinical signs of recurrence, should be regarded as a recurrence. AFP was found to be a useful tumor marker for the diagnosis and management of malignant germ cell tumors of the ovary.

Clinical behavior of borderline ovarian tumors : A Study of 150 cases

We evaluated the clinical features, treatment, and survival status of the patients with borderline ovarian tumors.

Mucinous Carcinoma of the Ovary

Since the incidence of mucinous carcinoma of the ovary is relatively low, with only small numbers of cases at any institution, detailed clinicopathologic studies on the prognosis and the care of patie

IMMATURE TERATOMA OF THE OVARY

The purpose of this study was to establish the optimal management of immature teratoma of the ovary. Pursuant to this, 20 previously untreated patients with immature teratoma were evaluated. Nine patients were at stage I of the disease, 2 had progressed to stage II, and 9 to stage III. Eight patients had grade 1 tumors, 11 had grade 2 tumors, and 1 had a grade 3 tumor. Postoperative chemotherapy was performed in 19 cases. Vincristine, actinomycin D, and cyclophosphamide (VAC) were administered in 9 cases, chemotherapy including cisplatin (P) was administered in 8 cases, and other regimens were followed in the 2 remaining cases. The median follow-up period was 62 months (range 19-108 months), and no patient was lost to follow-up. After completion of the follow-up period, 18 patients were alive and disease free, 1 was alive with liver metastasis, and 1 had died. The patient who died had suffered from a grade 3 tumor, and the recurrent tumor was a rhabdomyosarcoma. As a result of this study, it was found that immature teratoma of grades 1 and 2 can be managed successfully with VAC or P therapy. Thus, a hysterectomy should not be automatically performed in patients who still hope to give birth, yet suffer from a grade 1 or 2 immature teratoma at the time of a second operation.

Growth inhibitory effect of bestatin on choriocarcinoma cell lines in vitro

Bestatin, one of the biological response modifiers (BRMs), is an inhibitor of aminopeptidase B (AP-B), leucine aminopeptidase (LAP) and aminopeptidase M (AP-M). In this report, we investigated the direct effect of bestatin on the growth of cancer cellsin vitro using established four choriocarcinoma cell lines.in vitro chemosensitivity was evaluated by the succinate dehydrogenase inhibition (SDI) test. Bestatin showed the growth-inhibitory effect on all the choriocarcinoma cell lines dose-dependently, especially on NaUCC-4 cells. Both an isomer of bestatin with no inhibitory activity against aminopeptidases, (2R, 3S)-AHPA-(R)-Leu, and another isomer with stronger inhibitory activity against AP-B than bestatin, (2S, 3S)-AHPA(R)-Leu, did not show growth inhibition on NaUCC-4 cells. So it is suggested that one of the possible mechanisms responsible for the direct action of bestatin on the choriocarcinoma cells may be related to the inhibition of activity of LAP or AP-M rather than that of AP-B. Furthermore, cytotoxicity of actinomycin D on the choriocarcinoma cells was significantly enhanced by combination with bestatin. These results suggest that bestatin has not only an indirect host-mediated anti-tumor activity, but also a direct growth-inhibitory effect on some kinds of cancer cell lines.

A Randomized Trial of Cisplatin, Vinblastine, and Bleomycin versus Cyclophosphamide, Aclacinomycin, and Cisplatin in Epithelial Ovarian Cancer

After primary cytoreductive surgery, a randomized clinical trial was conducted in women with epithelial ovarian cancer to compare the impact on survival between PVB chemotherapy, consisting of cisplatin, vinblastine and bleomycin, and CAP chemotherapy, consisting of cyclophosphamide, aclacinomycin and cisplatin. There were 148 evaluable patients. One hundred and five patients with stage II, III and IV were analyzed in this study, 49 of them received PVB chemotherapy while the remaining 56 patients received CAP chemotherapy. Sixty-four patients fulfilled the criteria for clinical remission set by the Tokai Ovarian Tumor Study Group [Gynecol Oncol 1993;48:342-348]. The remission rate was 73 and 50% in the PVB and CAP groups, respectively, and showed a significant advantage for the PVB group (p = 0.0139). Moreover, the recurrence rate was 44% in the PVB group and 61% in the CAP group after clinical remission, although there was no significant difference between the two groups. The final survival rate was 32% in the PVB group and 24% in the CAP group. There was a significant difference of survival rate between both groups at 24 months (p = 0.0378) and 48 months (p = 0.0450), but finally no significant difference was found at 96 months (p = 0.0660). Compared to the CAP regimen, the PVB combination has a significantly higher efficacy in remission, but there was no significant difference in the long-term survival rate. Furthermore, multivariate analysis demonstrated that the PVB chemotherapy improved the survival, but it was not significant. The authors conclude that PVB chemotherapy may be more effective than CAP chemotherapy for epithelial ovarian cancer.

Mitomycin C cross-resistance induced by Adriamycin in human ovarian cancer cells in vitro

SummaryWe prepared Adriamycin-resistant cancer cells by exposing an ovarian serous cystadenocarcinoma cell line to the drug. The resistant cells also showed cross-resistance to a wide variety of other compounds, including vincristine, vinblastine, actinomycin D, daunorubicin, mitomycin C and carboquone. Against vincristine, the cells showed a >5,000-fold increase in resistance, far surpassing their resistance to the selection drug. The resistant cells displayed a decrease in intracellular Adriamycin content and an increase in the mRNA of themdr-1 gene coding for P-glycoprotein, with no amplification of the DNA. In revertant cells, resistance to Adriamycin was lost, but that to mitomycin C was maintained. Adriamycin resistance was partially overcome by the addition of verapamil or cyclosporin A, but cross-resistance to mitomycin C was not influenced at all. These results strongly suggest that the resistance to mitomycin C observed in our Adriamycin-resistant cells was due to some other mechanism than that causing multidrug resistance.

Sequence‐dependent Termination of Mammalian DNA Polymerase Reaction by a New Platinum Compound, (–)‐(R)‐2‐Aminomethylpyrrolidine(1,1‐cyclobutane‐dicarboxylato)‐2‐platinum(II) Monohydrate

We examined the mechanisms of the inhibition of DNA synthesis by a new platinum compound, (‐)‐(R)‐2‐aminomethylpyrrolidine(1,1‐cyclobutane‐dicarboxylato)‐2‐platinum(II) monohydrate (DWA‐2114R), a derivative of the antitumor drug cis‐ diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA‐2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose‐dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second‐strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase α were strongly arrested at guanine‐guanine sequences (GG). Stop bands were also observed at adenine‐guanine sequences (AG) guanine‐adenine‐guanine sequences (GAG) and mono‐guanine sequence (G). Calf testis DNA polymerase β was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.

Accumulation of cis-diamminedichloroplatinum (II) and its analogues in sensitive and resistant human ovarian carcinoma cells.

Human ovarian carcinoma cell line (NOS2), established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise increase in cis-diamminedichloroplatinum (II) (CDDP) concentration to produce a CDDP-resistant cell line NOS2CR) as an experimental model for resistance to CDDP. NOS2CR cells showed a 7-fold resistance to CDDP and a lesser degree of cross-resistance to diammine (1,1-cyclobutanedicarboxylato)-platinum (II) (CBDCA) and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) (DWA2114R). In the absence of CDDP, cross-resistance to DWA2114R was reduced to the original level by 2 months, although 83% resistance to CDDP remained up to 6 months. To investigate CDDP-resistant mechanisms, alterations in the intracellular accumulation of CDDP and analogues were assayed by atomic absorption. In both NOS2 and NOS2CR cells, accumulation of CDDP increased linearly with time and was concentration-dependent. NOS2CR cells demonstrated 71, 52 and 12% reduction in accumulation of CDDP, CBDCA, and DWA2114R, respectively. These reductions did not seem to be due to P-glycoprotein, because expression of multidrug-resistant 1 gene was not detected in either NOS2 or NOS2CR cells. These studies indicate that the mechanisms of resistance to CDDP and analogues in NOS2CR cells are related in the main to reduced intracellular accumulation of drugs. DWA2114R might be helpful to treat CDDP-resistant and recurrent tumors which were treated by CDDP.