Structure-activity relationships for the formation of secondary radicals and inhibition of keratinocyte proliferation by 9-anthrones.

The biological properties of tumor-promoting and antipsoriatic 9-anthrones have been hypothesized to be mediated by free radical products such as the corresponding 9-anthron-10-yl radicals or by O2-, OH, and other persistent secondary radicals that are formed in the skin after topical treatment with 9-anthrones. To gain additional insights into the possible role of reactive oxygen or secondary radicals in mediating the biological effects of 9-anthrones, we have used EPR spectroscopy to investigate the formation of these species by a series of 9-anthrones or 9-anthrone dimers with known tumor-promoting and antipsoriatic activities. The effect of the 9-anthrones on keratinocyte proliferation in vitro was also investigated. 5,5-Dimethyl-1-pyrroline N-oxide was used as a spin trap to detect reactive oxygen-centered radicals in aqueous buffer/dimethylsulfoxide solutions. Super-radicals in aqueous buffer/dimethylsulfoxide solutions. Superoxide was trapped during the autoxidation of most of the 9-anthrones. For 9-anthrones that generated no detectable superoxide, evidence of anthronyl-peroxyl radical formation was found instead. In the presence of Fe3+ complexed to EDTA, but not diethylenetriaminepentaacetic acid, the hydroxyl radical was produced by all of the 9-anthrones. 9-Anthrone dimers produced oxygen-centered radicals only weakly or not at all. Direct EPR was used to detect 9-anthrone-derived secondary radicals in keratinocyte suspensions or in dimethysulfoxide solutions. These radicals were similar to those previously reported to occur in skin after topical treatment with the antipsoriatic drug anthralin (1,8-dihydroxy-9-anthrone). In contrast to the ubiquitous ability of the 9-anthrones to generate reactive oxygen radicals, only the hydroxy-substituted 9-anthrones or their dimers possessed significant secondary radical-forming ability. The ability of the 9-anthrones or dimers to form secondary radicals in keratinocytes was found to correlate with their in vitro inhibition of keratinocyte proliferation. The data suggest the possible importance of reactive dimeric intermediates in mediating the biological effects of the 9-anthrones.

The management of ovarian carcinoma is improved by the use of cancer-associated serum antigen and CA 125 assays.

BACKGROUND: The new tumor-associated mucin assay, cancer-associated serum antigen (CASA), was assessed with the CA 125 assay for use in the management of patients with epithelial ovarian cancer. METHODS: CASA and CA 125 were assessed retrospectively for use in (1) monitoring 28 patients with Stage 3 or 4 ovarian carcinoma during therapy, (2) predicting the outcome of 41 second-look laparotomies (SLL), and (3) predicting the survival outcome by measuring these levels after surgery but before chemotherapy in 65 patients with Stage 3 disease. RESULTS: Of 20 patients with recurrence after an initial response, the presence of CASA levels detected recurrence in 65% before clinical detection; CA 125, 50%; and the combination of CASA and CA 125, 80%. Six patients whose disease was in long-term remission did not have elevations of either marker. When used to predict the results of SLL, the positive predictive values of CASA and CA 125 were 77% and 100%, respectively. The negative predictive values for CASA and CA 125 were 71% and 66%, respectively. CASA detected 50% of positive SLL where microscopic disease only was found; the CA 125 test did not. Multivariate analysis of survival rates using levels of CASA and CA 125, age, residual disease, tumor type and grade, or the presence or absence of cisplatin in the chemotherapeutic regimen found that postoperative CASA levels ranked above all prognostic factors except age. CASA levels may be more accurate than surgical reporting of residual disease or they may define a subset of patients with biologically more aggressive ovarian carcinoma. CONCLUSIONS: The CASA test is sensitive to ovarian carcinoma, and both CASA and CA 125 are more useful when used in conjunction.

Carcinoma of the cervix-recurrences in Queensland 1982-1986.

A retrospective study of recurrent cancer of the cervix was carried out on patients who attended the Gynaecologic Oncology Unit, Royal Brisbane Hospital, between the years 1982 and 1986. Ninety-four recurrences were assessed out of 526 patients (17.7%). The likely recurrence was related to stage. Sixty-seven percent had pelvic recurrences with 33% recurring in extrapelvic sites alone. The most common site of tumor recurrence was central pelvis (47%). Histopathology recurrences were analyzed and recurrence was found to be more common with the rare tumor types. Mortality of recurrent carcinoma of the cervix is high. Multivariate analysis shows lymph node metastases and histologic status of resection margins to be independent variables predictive of recurrence. Lymphvascular space involvement has not been an independent variable after adjusting for nodes and margins. Cytology of vaginal vault or residual cervix smear shows that 58% of patients with central recurrence had an abnormal smear. The relative literature was discussed in relation to the findings of our unit.

Preoperative discrimination between ovarian carcinoma, non-ovarian gynecological malignancy and benign adnexal masses using serum levels of CA125 and the polymorphic epithelial mucin antigens CASA, OSA and MSA.

Serum levels of the tumor associated antigens CA125, CASA, OSA and MSA were determined preoperatively in a non-consecutive series of patients with: invasive epithelial ovarian cancer (OC, n = 87), ovarian tumors of low malignant potential (LMP, n = 9), benign adnexal masses (BAM, n = 48) and other peritoneal and pelvic malignancies (n = 48). In addition, serum levels of CASA, OSA, and MSA were determined in 3477 asymptomatic well women. Ninety-eight percent of the asymptomatic women had CASA levels < 6.0 U ml-1, OSA levels < 5.5 U ml-1 and MSA levels < 80.0 U ml-1. Serum CA125 levels were> 35 U ml-1 in 89% of OC, in 44% of LMP, and in 23% of BAM. Serum CASA levels were> 6.0 U ml-1 in 58% of OC, in 0% of LMP, and in 0% of BAM. Serum OSA levels were> 5.5 U ml-1 in 61% of OC in 0% of LMP and in 4% of BAM. Serum MSA levels were> 80.0 U ml-1 in 56% of OC, in 11% of LMP, and in 10% of BAM. When cut-off levels were set to exclude all patients with BAM, the best discrimination from OC using a single assay was achieved using CASA (58%). However, a combination of CASA and CA125 gave positive levels in 69% of OC at levels which precluded BAM. All markers were also elevated in some colon cancers, cervical cancers, uterine cancers and other peritoneal malignancies. A combination of CA125 and CASA levels, obtained preoperatively may assist the general gynecologist in avoiding potentially difficult oncologic surgery.