[The clinical and pharmacokinetic evaluation of two-route chemotherapy with cisplatin and sodium thiosulfate in combination with angiotensin II].

Thirty-six courses of chemotherapy with cisplatin (CDDP) and sodium thiosulfate (STS) were performed in 31 patients with gynecologic cancer 2 weeks after operation under the hypertensive condition induced by angiotensin II (AT-II). One hundred-fifty mg of CDDP/body was intraperitoneally administered while the usual systolic blood pressure was increased to 130-140% by AT-II. The hypertension was maintained for 15 minutes after finishing CDDP infusion, then 8g of STS was intravenously infused immediately after the cessation of AT-II. The urinary Pt level measured 15 minutes after finishing CDDP infusion was extremely low at 1.37 +/- 0.47 micrograms/ml, in spite of the significantly high levels of plasma total Pt (7.83 +/- 0.85 micrograms/ml) and filtrable Pt (4.02 +/- 0.55 micrograms/ml). This suggests that, during renal vasoconstriction induced by AT-II, the renal blood flow as well as renal uptake of CDDP was decreased. Plasma filtrable Pt levels were measured at 15, 30, 60 and 120 minutes after intraperitoneal administration of CDDP. At 15 and 30 minutes a significantly higher blood concentration was found than in the control group (p less than 0.05). However, CDDP-induced toxicities of the bone marrow, liver, kidney and alimentary tract were not increased. The extreme vasoconstriction in the kidneys and other organs induced by AT-II might have protected these organs from the toxicities of CDDP despite the fact that STS infusion was delayed by 15 minutes after CDDP infusion. STS infused immediately after the cessation of AT-II could neutralize the CDDP preventing the occurrence of toxicities.(ABSTRACT TRUNCATED AT 250 WORDS)

[The diminishing oocyte toxicity following intraperitoneal infusion of cisplatin (CDDP) combined with subcutaneous injection of sodium thiosulfate (STS) in syngeneic young mice].

Small oocytes in 6-week-old C57BL/6 mice were destroyed in a dose-dependent fashion following intraperitoneal infusion of CDDP. ED65, the effective dose of which theoretically produced 65% destruction of small oocytes according to Probit analysis, was determined as 0.2mg/mouse. In this study, the oocyte toxicity induced with intraperitoneal treatment with CDDP (0.2mg) was offset by subcutaneous treatment with STS (40mg, 400 x molar ratio compared to that of CDDP). STS was subcutaneously injected into the back skin of mice at 60, 30, 15 minutes before, at the same time or at 15, 30, 60 minutes after the CDDP injection. STS markedly diminished the oocyte toxicity and reduced oocyte destruction about 45% when it was injected at 30, 15 minutes before or at the same time as CDDP infusion. On the other hand STS failed to reduce oocyte destruction when it was injected 15, 30 or 60 minutes later. STS might neutralize CDDP in the circulating blood to decrease the amount of active CDDP, but STS might not have any effect on CDDP once it is incorporated and conjugated with the DNA in the oocytes.

[The hypertensive effect induced with angiotensin II and the physiological and pharmacokinetic aspects of two-route chemotherapy using CDDP and STS].

Two-route chemotherapy of CDDP and STS was performed in 16 postoperative patients with ovarian cancer under the hypertensive condition of 20 minutes induced with angiotensin II (AT-II). Plasma total CDDP and filtrable CDDP levels serially determined at 15 and 30 minutes after intraperitoneal administration of CDDP (150 mg/body) were significantly higher than under the same condition except for using AT-II. The extreme vasoconstriction in the kidney and other organs during AT-II induced hypertension would protect these organs from CDDP induced toxicities. Furthermore, STS infused immediately after the cessation of AT-II could neutralize the CDDP preventing the occurrence of toxicities. The elevating plasma levels of CDDP might be beneficial to enhance the anticancer effects of CDDP, since the blood flow in cancer tissue was increased during AT-II induced hypertension.

[Localization of sex steroid hormone and sex steroid hormone receptors in human ovarian epithelial tumor].

In some ovarian tumors, such as endometrioid adenocarcinoma, dysfunctional uterine bleeding occurs, and the endocrinological aspects were studied in the following way: 1) In 3 patients with epithelial ovarian tumor and postmenopausal uterine bleeding, preoperative plasma estradiol (E2) and progesterone (P) concentrations were significantly high, but dropped to normal following complete resections of the ovarian tumor. Plasma E2, P and testosterone concentrations in ovarian veins were 3 to 7 times as great as in peripheral veins. 2) Tissues obtained from 25 ovarian tumors were immunohistochemically examined by the PAP method. In 9 cases of endometrioid adenocarcinoma, positive stainings for both E2 and P were demonstrated in cancer cells from 3 patients (33%) and in connective tissues from 7 patients (78%), respectively. In contrast, 16 tumors of other histological types gave only one positive staining for E2 on cancer cells and connective tissues. As for P, in 3 patients there was a positive stain on cancer cells and in 2 patients on connective tissues. 3) Five out of 8 patients with immunohistochemically positive staining for E2 on connective tissues in ovarian tumors demonstrated dysfunctional uterine bleeding. 4) Cytosolic estrogen receptor (ER) and progesterone receptor (PR) in ovarian tumors obtained from 26 patients were measured by the DCC method. All of three patients with endometrioid adenocarcinoma had both ER and PR. The former were 19-202 fmol/mg, and the latter 535-1,000 fmol/mg, which were significantly higher levels and positive rates than those from other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Quantitative evaluation for murine oocyte toxicity following intraperitoneal treatment with chemotherapeutic agents].

The ovarian toxicity induced with 12 oncostatics was evaluated using syngeneic mice, 6-week-old C57BL/6. Each drug diluted with saline to 0.2ml was intraperitoneally infused twice at 6 and 7 weeks old. Mice were sacrificed 2 weeks after the second treatment, the ovaries removed and fixed for serial sectioning, and the small oocytes of Pedersen and Peters counted. Small oocytes were destroyed in a dose-dependent fashion, and ED50, an effective dose of which produced 50% destruction of small oocytes in each mice group, was significantly divided into 4 groups of statistical difference (F = 5.77, p less than 0.0213). The smallest dose of ED50 (mg/mouse) (the strongest in oocyte toxicity): Actinomycin D 0.0064, doxorubicin 0.0184, peplomycin 0.021; the second: Bleomycin 0.107, mitomycin 0.0707, CDDP 0.120; the third: Cyclophosphamide 0.427; and the largest (the weakest): Ifosphamide 3.01, 5FU 6.17, etoposide 6.11, methotrexate 2.0 much less than, vinblastine 0.1 much less than. The most toxic included those which could attack not only DNA, but also RNA biosynthesis and the least included those which could have an effect on enzymes or proteins with no direct action on DNA. The ratio of ED50 to HUD, the single usual dose for human cancer chemotherapy, were smallest for doxorubicin (2.23), cyclophosphamide (2.59) and CDDP (5.19). Although these three are very useful oncostatics for ovarian cancer, they might have serious potential toxicity for human ovarian oocytes.

[Augmentative effects of radiofrequency hyperthermia (RFH) combined with intraperitoneal (IP) administration of CDDP in ovarian cancer].

Radiofrequency hyperthermia (RFH) was applied to 21 adnexal cancer patients in combination with IP administration of CDDP (150 to 200 mg) 2 weeks or more after surgery. The instrument used, an OMR-ON HEH 500C, was shown by rectal temperature monitoring to produce sufficient intraperitoneal temperature elevation up to 40 degrees-41 degrees C. The serum level of filterable CDDP after IP infusion of CDDP (150 mg) followed by sodium thiosulfate rescue was basically the same irrespective of whether RFH was used. It reached a peak level of 2.06 +/- 0.48 micrograms/ml (n = 8) 1h after IP infusion, and gradually declined thereafter. No serious side effect except 3 cases of II- to III-degree burns was recognized. A slight increase in the incidence of prolonged vomiting and diarrhea was found with the RFH combination. This suggests an exacerbating effect of RFH on intestinal damage following CDDP infusion. As for any suppressive effect on reaccumulation of ascites, RFH might have a slight benefit in increasing the antitumor effect of CDDP in 90% of patients.

[Estimation of 1-hexylcarbamoyl-5-fluorouracil (HCFU) and 5-FU concentrations in sera and resected specimens from patients with ovarian tumors].

Concentrations of HCFU and 5-FU in blood and tissues of resected specimens were evaluated in 28 patients with ovarian tumor (pathologically benign 10, malignant 18) preoperatively considered to be malignant. 1) No significant difference of HCFU and 5-FU concentrations in sera, uterus and peritoneum was observed between the benign and cancer groups. 2) No significant difference of HCFU concentration in tissues of ovarian tumor was recognized between the benign and malignant groups, but as for 5-FU concentrations, 0.116 +/- 0.198 micrograms/g tissue in the cancer group was considerably higher than 0.021 +/- 0.144 micrograms/g tissue in the benign group (p = 0.085). Furthermore, the 5-FU level in ovarian cancer tissues was much higher than that in the tissues of the contralateral normal ovary, suggesting that degradation of 5-FU might be delayed in cancer tissue. 3) HCFU concentration in omental tissues from cancer patients was 0.043 +/- 0.061 micrograms/g tissue, significantly higher than that from benign patients, 0.004 +/- 0.008 micrograms/g tissue (p = 0.024). As for 5-FU concentration, no apparent difference was found, suggesting that 5-FU might be quickly eluted or metabolized in omental tissue.