Activity In Ovarian Cancer Research Articles

Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts.

The objective of this study was to investigate the cytotoxic activity of irofulven (HMAF, MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of ovarian cancer. Antiproliferative effects of irofulven in ovarian cancer cell lines and ovarian tumor specimens were characterized in vitro using sulforhodamine B and human tumor colony-forming assays, respectively. Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human tumor cloning assays, irofulven inhibited colony formation in surgically derived ovarian tumors at concentrations as low as 0.001 micro g /ml and indicated superior activity in comparison with paclitaxel when tested against the same tumor specimens. The antitumor activity of irofulven compared to that of paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3 tumors, treatment with paclitaxel failed to inhibit tumor growth; whereas mice treated with maximum tolerated doses of irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean tumor growth inhibition of 82%. The potent activity of irofulven against ovarian tumors in vitro and in vivo supports the evaluation of its clinical activity in ovarian cancer.

Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts

The objective of this study was to investigate the cytotoxic activity of irofulven (HMAF, MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of ovarian cancer. Antiproliferative effects of irofulven in ovarian cancer cell lines and ovarian tumor specimens were characterizedin vitrousing sulforhodamine B and human tumor colony-forming assays, respectively. Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human tumor cloning assays, irofulven inhibited colony formation in surgically derived ovarian tumors at concentrations as low as 0.001 μg /ml and indicated superior activity in comparison with paclitaxel when tested against the same tumor specimens. The antitumor activity of irofulven compared to that of paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3 tumors, treatment with paclitaxel failed to inhibit tumor growth; whereas mice treated with maximum tolerated doses of irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean tumor growth inhibition of 82%. The potent activity of irofulven against ovarian tumorsin vitroandin vivosupports the evaluation of its clinical activity in ovarian cancer.

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with advanced epithelial ovarian cancer. A phase II trial of sequential doublets. (GO-FIRST)

5034 Background: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity, and in pre-clinical studies have shown synergy. The primary objective of this prospective phase II study is to evaluate the response rate (RR) and toxicity of gemcitabine and oxaliplatin (GO) administered sequentially with paclitaxel and carboplatin (PC). Secondary objectives were time to progression, quality of life outcomes and overall survival. Methods: Patients with histologically proven epithelial ovarain cancer, FIGO stage II-IV, measurable disease (RECIST), and PS 0–2 were eligible. Treatment consisted of gemcitabine 1250mg/m2 D1, D8 and oxaliplatin 135mg/m2 D8 q21days for 4 cycles followed by carboplatin AUC6 and paclitaxel 175mg/m2 D1 q21days for 4 cycles. Interval debulking was permitted after 4 cycles. Results: 20 patients are enrolled. Median age 62 yrs (range 39–78), FIGO III-IV (16/4). 12/20 pts were only able to have an initial biopsy and of these, 7 were subsequently debulked. 4 cycles of GO were given prior to the planned 4 cycles of PC. The RR to 4 cycles of GO was 80% (CR4/PR12). With subsequent debulking surgery and further chemotherapy (PC) the final RR was 85% (13 CR/4 PR). One pt died of a PE and one progressed on GO and died. At a median F/U of 21 mths 15 pts are still alive, 6 without progression. The median TTP was 15.2 mths. Grade 3/4 toxicities for GO: nausea and vomiting 4pts (20%), neutropenia 4pts (20%). PC: alopecia 14 (70%), neutropenia 2 (10%), thrombocytopenia 1 (5%). Peripheral neuropathy was the major toxicity. 4 pts developed G2 and a further 1pt G3 on GO. With sequential PC, 8 pts developed G2 and 5 pts G3 neuropathy requiring dose reduction in 3 pts and cessation of paclitaxel in 6 pts. Conclusions: GO is a new doublet with activity in ovarian cancer, but sequential PC should not be used given the cumulative neurotoxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly

Gemcitabine (GEM) + oxaliplatin (OX) in patients (pts) with stage III/IV ovarian cancer following 3 cycles of carboplatin (CB) + paclitaxel (PAC): Preliminary report of a phase II study

5111 Background: GEM is active in recurrent epithelial ovarian cancer. OX activity in ovarian cancer is similar to cisplatin in first-line therapy and PAC in nonrefractory relapses. This multicenter, prospective phase II study combines GEM/OX as first-line sequential therapy for advanced ovarian cancer in pts after 3 cycles of CB/PAC. Primary endpoint is time to disease progression; secondary endpoints are CA 125 response rate, objective response, response duration, overall survival, correlation between expression of MMR and p53 and efficacy, and toxicity. Methods: Pts with confirmed histologic diagnosis of stage III/IV epithelial ovarian carcinoma, initial surgery including anexohysterectomy + omentectomy, 3 cycles of CB ≥AUC 5 and PAC ≥175 mg/m2, no other prior chemotherapy, and adequate organ and marrow function were enrolled. Three to 4 weeks after CB/PAC, pts received GEM 1000 mg/m2 on days (d) 1,15 (100-minute infusion) and OX 85 mg/m2 on d2,16 (120-minute infusion), q28d. Results: To date, 18 pts (median age 57 [range 42–73]; Zubrod performance status 0/1 [10/8 pts]) have been enrolled. 8 pts had stage IIIB; 7, stage IIIC; 3, stage IV. At baseline, median CA 125 level was 777 ng/ml (range 27–9330). Of 13 evaluable for CA 125 response, 12 had complete response and 1 progressed; 3 were evaluable for objective response (1 complete and 2 partial). Total number GEM/OX cycles was 51 (median 2.83 [range 1–3]). All intended doses given as planned; only 5.8% were delayed due to insufficient hematologic recovery. All were evaluable for toxicity. Grade (G) 3 anemia occurred in 2 cycles (3.9%); G3 neutropenia, in 1 cycle (1.9%); mild thrombocytopenia (G1), in 4 cycles (7.8%). G3 nausea occurred in 1 cycle (1.9%); G3 vomiting, in 2 cycles (3.9%). Reversible G1/2 sensory neuropathy occurred in 9 (17.6%) and 3 cycles (5.9%), respectively. No treatment-related deaths occurred. Conclusions: GEM/OX following CB and PAC is feasible, with minimal and manageable toxicity, in pts with ovarian cancer. Updated results of survival and pharmacology will be presented. Supported by Eli Lilly, Debiopharm. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly

Gemcitabine (GEM) + oxaliplatin (OX) in patients (pts) with stage III/IV ovarian cancer following 3 cycles of carboplatin (CB) + paclitaxel (PAC): Preliminary report of a phase II study

5111 Background: GEM is active in recurrent epithelial ovarian cancer. OX activity in ovarian cancer is similar to cisplatin in first-line therapy and PAC in nonrefractory relapses. This multicenter, prospective phase II study combines GEM/OX as first-line sequential therapy for advanced ovarian cancer in pts after 3 cycles of CB/PAC. Primary endpoint is time to disease progression; secondary endpoints are CA 125 response rate, objective response, response duration, overall survival, correlation between expression of MMR and p53 and efficacy, and toxicity. Methods: Pts with confirmed histologic diagnosis of stage III/IV epithelial ovarian carcinoma, initial surgery including anexohysterectomy + omentectomy, 3 cycles of CB ≥AUC 5 and PAC ≥175 mg/m2, no other prior chemotherapy, and adequate organ and marrow function were enrolled. Three to 4 weeks after CB/PAC, pts received GEM 1000 mg/m2 on days (d) 1,15 (100-minute infusion) and OX 85 mg/m2 on d2,16 (120-minute infusion), q28d. Results: To date, 18 pts (median age 57 [range 42–73]; Zubrod performance status 0/1 [10/8 pts]) have been enrolled. 8 pts had stage IIIB; 7, stage IIIC; 3, stage IV. At baseline, median CA 125 level was 777 ng/ml (range 27–9330). Of 13 evaluable for CA 125 response, 12 had complete response and 1 progressed; 3 were evaluable for objective response (1 complete and 2 partial). Total number GEM/OX cycles was 51 (median 2.83 [range 1–3]). All intended doses given as planned; only 5.8% were delayed due to insufficient hematologic recovery. All were evaluable for toxicity. Grade (G) 3 anemia occurred in 2 cycles (3.9%); G3 neutropenia, in 1 cycle (1.9%); mild thrombocytopenia (G1), in 4 cycles (7.8%). G3 nausea occurred in 1 cycle (1.9%); G3 vomiting, in 2 cycles (3.9%). Reversible G1/2 sensory neuropathy occurred in 9 (17.6%) and 3 cycles (5.9%), respectively. No treatment-related deaths occurred. Conclusions: GEM/OX following CB and PAC is feasible, with minimal and manageable toxicity, in pts with ovarian cancer. Updated results of survival and pharmacology will be presented. Supported by Eli Lilly, Debiopharm. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly

Octreotide: an active agent in epithelial ovarian carcinoma?

Somatostatin is a naturally occurring small peptide that binds to five subtypes of cell-surface receptors, causing activation of secondary-messenger pathways via membraneassociated G proteins. Somatostatin analogues, such as octreotide, are useful for treatment of neuroendocrine tumours, but there are no reports of therapeutic activity for ovarian cancer, despite preclinical data that suggests that octreotide has antiproliferative activity in ovarian cancer cells and that somatostatin receptors are present in human ovarian-cancer samples. This case report discusses a patient with chemoresistant ovarian cancer who, after receiving four different schedules of chemotherapy and progressing through the last two, achieved a complete response while receiving octreotide in the absence of any cytotoxic chemotherapy.

Use of tamoxifen in asymptomatic patients with recurrent small-volume ovarian cancer

Objectives. Tamoxifen, a well-tolerated oral hormonal agent with biological activity in ovarian cancer, is a potentially attractive option in asymptomatic patients with recurrent disease. Unfortunately, the clinical utility of the drug in this specific setting has not been well documented. Patients and methods. A retrospective review was conducted of patients with cancers of the ovary, fallopian tube, and primary cancer of the peritoneum at the Cleveland Clinic who experienced recurrence of the malignancy, in the absence of large volume disease (by physical exam and radiographic evaluation) or any cancer-related symptoms, and who received tamoxifen (20 mg [most patients] or 40 mg/day) before re-initiation of cytotoxic chemotherapy. Results. Fifty-six patients (45 after primary chemotherapy; 12 after second-line treatment) satisfied the criteria noted above. The median duration of treatment was 3 months (range 1–30 months), with 42% and 19% of patients remaining on tamoxifen for ≥6 and ≥12 months, respectively. Reasons for discontinuation were equally divided between three causes: (a) continued rise in CA-125 antigen level without symptoms or other objective signs of cancer; (b) evidence of progressive disease by physical exam or radiographic evaluation in the absence of symptoms; and (c) development of cancer-related symptoms. Conclusion. In the absence of data from a randomized controlled trial which defines optimal management of the asymptomatic ovarian cancer patient with documented recurrent disease, tamoxifen is a rational management option, although it remains unknown if the delay in subsequent administration of chemotherapy in some individuals for periods greater than 6–12 months results from a direct effect of this agent or simply reflects the natural history of disease in a subset of patients in this clinical setting.

Role of intraperitoneal chemotherapy in the front-line setting.

During the last several decades, clinical investigators have confirmed the safety and pharmacokinetic advantage associated with the intraperitoneal delivery of a number of antineoplastic agents with known activity in ovarian cancer. Phase II experience has revealed that objective responses, including surgically documented complete remissions, can occur when regional drug delivery is used as second-line treatment of this malignancy. Three randomized trials have shown that when cisplatin-based intraperitoneal treatment is used in the front-line setting, it results in superior progression-free and overall survival compared with intravenous cisplatin. Despite these facts, an ultimate role for regional drug delivery as initial treatment of ovarian cancer will require additional trials to define how to optimize the use of this unique therapeutic strategy.

Procollagen-derived biomarkers in malignant ascites of ovarian cancer. Independent prognosticators for progression-free interval and survival.

Matrix formation is a hallmark of solid tumor biology. Circulating antigens of structural matrix proteins should reflect this fact, yet are subject to systemic variables. We propose that if measured regionally, in a cancer-induced extravascular fluid pool such as malignant ascites of ovarian cancer, the same antigens retain their conceptual advantage as surrogate markers for tumor biology. In malignant ascites obtained at staging laparatomy of 35 women with ovarian cancer, the protein-normalized levels of the C-terminal propeptide of procollagen type I (pnPICP) and the N-terminal propeptide of procollagen type III (pnPIIINP) were determined. Using univariate and multivariate analysis, we examined these parameters, their (pnPIIINP/pnPICP) quotient, and clinical criteria (FIGO stage, age, residual tumor, histology, and tumor grade) for impact on progression-free interval and survival. The absolute level of pnPIIINP was the single most powerful independent factor impacting on survival, its P value being distinctly below (P = 0.0005 vs 0.003) and its risk ratio distinctly above (15 vs 2.5) residual tumor after debulking surgery. The relative level of pnPIIINP, i.e. (pnPIIINP / pnPICP), impacted on the likelihood of recurrence even more than residual tumor. By Kaplan-Meier analysis, cutoff values for the absolute or relative pnPIIINP level significantly discriminated patients with shortened survival or progression-free interval, respectively. Since malignant ovarian epithelium itself forms collagen type III, and since collagen type III is a solid-phase regulator of angiogenesis, we propose that ascitic pnPIIINP is a fluid-phase indicator for angiogenic activity in ovarian cancer and thus represents a tumor virulence index.

Epithelial ovarian cancer: Second and third line chemotherapy (Review)

Standard therapy for patients affected with advanced epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy. With this treatment, most patients obtain clinical complete or partial response, nevertheless, relapse is common and salvage chemotherapy is often needed. The probability of response to second line chemotherapy following platinum-based treatments is usually related to the platinum-free interval, even if recent studies have reported some other clinical features as having prognostic value, such as tumour burden and histology. Salvage monochemotherapy is generally used, but when the platinum-free interval is longer than 24 months, re-treatment with platinum compounds and/or taxanes is indicated. Moreover, a number of new agents with demonstrated activity in ovarian cancer are currently available. Sequentially used in recurrent disease, these agents may improve survival and/or quality of life. Among these new drugs, the most promising are: topotecan, doxil, gemcitabine and platinum analogues such as oxaliplatin, nedaplatin, satraplatin, BBR3464 and ZD0473. However, the real aim of salvage chemotherapy in relapsed ovarian cancer still remains palliative care, because complete responses are very rarely reported and long lasting responses are very seldom observed.

PD 115934 exhibits moderate activity in ovarian cancer

PD 115934 exhibits moderate activity in ovarian cancer

Telomerase activity in gynecological tumors.

The aim of this study was to define the clinical implications of semi-quantitative telomerase activity in gynecological tumors by comparing the telomerase activity of cancerous lesion and the adjacent non-cancerous lesion. In 118 cases of gynecologic tumors, including 41 uterine cervical tumors, 43 uterine body tumors and 34 ovarian tumors, telomerase activities were determined using TRAPeze telomerase detection kit for the extension reaction of the telomere sequence and the PCR reaction for amplification of the sequence, and using fluorecence-based telomere repeat amplification protocol (F-TRAP) method for the detection. In all gynecologic cancers examined, telomerase activity of the cancerous lesion was significantly higher than that of the non-cancerous lesion. Telomerase activity in the uterine cervix increased in the following order of the normal uterine cervix, cervical dysplasia and cervical cancer. Regarding the endometrial cancer, telomerase activity at the primary lesion in patients with lymph node metastases was significantly higher than that in patients without lymph node metastases. When telomerase activity was compared by histologic subtypes of the ovarian cancer, clear cell adenocarcinoma showed significantly lower telomerase activity than the other subtypes, especially endometrioid adenocarcinoma. In all gynecologic cancers examined, there was no clear correlation between the telomerase activity and age at diagnosis or age of menopause. Although all tumors with 100 units or more telomerase activity were cancerous, the sensitivity was 39% in cervical cancer, 41% in endometrial cancer and 21% in ovarian cancer, respectively. Cervical intraepithelial neoplasia (CIN) had already increased telomerase activity and endometrial cancer with lymph node metastases had also greater activity than that without lymph node metastases. Although telomerase activity in ovarian cancer tended to increase as stage advances, it is noteworthy that clear cell adenocarcinoma showed significantly lower telomerase activity than endometrioid adenocarcinoma.

Alteration of Telomerase Activity in Ovarian Cancer after Chemotherapy

To elucidate the relationship between telomerase activity and chemosensitivity in epithelial ovarian cancer, telomerase activity and telomere length (TRF) were examined before and after chemotherapy. Of 21 patients, 9 patients responded to chemotherapy and 12 did not. The positivity of telomerase activity did not significantly differ between responders and nonresponders. There were no differences in the mean length and the distribution of TRF between the two groups. Those distributions became narrow after chemotherapy in both groups. Seven nonresponders (58.3%) exhibited an increase in telomerase activity after chemotherapy but none of the responders showed an increase in activity. Telomerase activity may relate to chemosensitivity in epithelial ovarian cancer.

Gemcitabine in the treatment of ovarian cancer

Gemcitabine in the treatment of ovarian cancer

Postconfluent multilayered cell line cultures for selective screening of gemcitabine.

The in vitro cytotoxicity of gemcitabine (dFdC) was tested in ovarian and colon cancer cell lines grown as monolayers and three-dimensional multilayered cell cultures. In our model, dFdC showed slight selectivity in cytotoxicity against ovarian over colon cancer cells, when cell lines were grown as monolayers. However, when cell lines were grown as multilayers, this selectivity was accentuated: A2780 multilayers were 14 times less sensitive than monolayers, but the colon cancer cell lines were more than 1000 times more resistant than their corresponding monolayers. The accumulation of the active metabolite, dFdCTP, after 24 h exposure to 1 microM dFdC varied between 1100 and 1900 pmol/10(6) cells in monolayers. This was 5 times lower in multilayers compared with monolayers of all four cell lines, which can, in part, explain the lower sensitivity of the multilayers. In addition, it appears that the amount of the active metabolite retained is more important than the amount accumulated initially, since the differences between the ovarian and the colon cancer cell lines were more evident in retention experiments. Exposure to dFdC caused a 2-3-fold increase in the levels of several nucleotides, except for the CTP pools in the colon cancer lines, which were reduced by 3-fold at the highest dFdC concentration (10 microM). The findings with the multilayer model are in better agreement with in vivo activity in ovarian cancer and colon cancer than those with the monolayer system. This indicates the potential of the multilayer system to be a better predictive model than the conventionally used monolayer cultures.

Chemotherapy of ovarian cancer.

The classic approach to the treatment of ovarian cancer has been the combination of cytoreductive surgery followed by chemotherapy. Surgery has played an instrumental role in the overall management of the disease because of the necessity for accurate staging and because of the finding that chemotherapy is more effective in patients who have small-volume disease after initial surgery. The vast majority of patients with ovarian cancer are diagnosed with stage III disease at a time when they have intraperitoneal carcinomatosis. While surgery is effective in removing the bulk of disease in 50–80% of patients, it is not a curative modality at this stage because the vast majority of patients are left with residual cancer. Ovarian cancer has long been known to be a chemosensitive tumor. Early studies demonstrated that drugs from different classes of chemotherapeutic agents (alkylating agents, antimetabolites, DNA alkylating drugs, etc.) all had activity in ovarian cancer. In the late 1960s and early 1970s, multiple combination chemotherapy regimens were developed utilizing the principle of combining drugs with different mechanisms of activity and nonoverlapping toxicities [1]. However, the development of the platinum compounds in the 1980s changed the nature of chemotherapy for this disease. Platinum compounds (either cisplatin or carboplatin) had the highest degree of activity in ovarian cancer and became the mainstay of treatment [2]. Numerous studies subsequently demonstrated that the addition of multiple drugs to platinum was not associated with any significant improvement and the standard of care became the two-drug combination of the platinum compound plus an alkylating agent. In practical terms, most patients were treated in the United States with the combination of carboplatin and cyclophosphamide.KeywordsOvarian CancerEpithelial Ovarian CancerOvarian Cancer PatientPlatinum CompoundRecurrent Ovarian CancerThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Phase II trials of docetaxel (Taxotere) in advanced ovarian cancer--an updated overview.

Docetaxel (Taxotere) has been studied at a dose of 100 mg/m2 i.v. as a one hour infusion every 3 weeks, in four phase II trials in patients with extensively pretreated ovarian cancer. A total of 340 patients were treated, including 256 patients in two separate EORTC (European Organization for Research and Treatment of Cancer) trials and 84 patients in two trials in the U.S.A. All patients had received prior cisplatin or carboplatin therapy and the treatment-free interval was less than 4 months in 155 patients. The overall response rate using conventional UICC criteria was 30% among 315 evaluable cases (95% confidence interval: 24-36%). Among 155 patients whose disease was most refractory (i.e. treatment-free interval was less than 4 months), the overall response rate was 28% (95% confidence interval: 19-36%). Response duration ranged from 4 to 17 months. Grade IV neutropenia was a common finding and fluid retention was observed. The incidence of febrile neutropenia ranged from 8 to 44% of patients with two deaths (i.e. 0.6% of the total treated) related to neutropenic sepsis. Docetaxel and paclitaxel (Taxol) have comparable activities in ovarian cancer. Ongoing studies with docetaxel include its use in patients as part of first-line therapy, as well as in patients refractory to paclitaxel. To prevent the development of fluid retention, these now involve the routine use of steroid prophylaxis. It is expected that docetaxel will prove to be an important addition to the drugs available for the treatment of ovarian cancer.

Modulation of 5-Fluorouracil with High-Dose Leucovorin Calcium: Activity in Ovarian Cancer and Correlation with CA-125 Levels

The purpose of this study was to estimate the response rate, response duration, and survival of patients with advanced ovarian cancer treated with a 132-hr continuous infusion of high-dose calcium leucovorin in combination with five consecutive daily bolus doses of 5-fluorouracil (5-FU) and to correlate changes in CA-125 levels with clinical and radiologic assessment of disease progression. Forty-six heavily pretreated patients [median number of previous chemotherapy regimens, 2.5 (range 1-7)] with advanced ovarian cancer received 132-hr continuous infusions of calcium leucovorin (500 mg/m 2/day) for 5 1 2 days, with daily bolus doses of 5-FU (370 mg/m 2/day) for 5 days beginning 24 hr after initiation of the calcium leucovorin. Twenty-three patients had clinically measurable disease and 23 had evaluable disease; CA-125 levels were performed prior to each treatment course and after the final course of therapy. One of 42 patients had a partial response to combination chemotherapy (duration, 8.9 months); 16/42 had stable disease [median duration, 4.9 months (range, 2.4-9.0 months)]. Toxicity of combination therapy included mild myelosuppression and stomatitis, similar to previously reported toxicity profiles for the 5-FU and calcium leucovorin combinations. Sensitivity of CA-125 levels as a single indicator of disease progression was 55%. The combination of infusional high-dose calcium leucovorin and 5-FU has little activity in refractory ovarian cancer. CA-125 levels incorrectly predict clinical disease activity in about one-third of cases and should not be the sole criterion for determination of clinical response when evaluating chemotherapeutic efficacy in heavily pretreated patients.

O6-methylguanine-DNA methyltransferase in ovarian malignancy and its correlation with postoperative response to chemotherapy.

O6-Methylguanine-DNA methyltransferase (MGMT) in human neoplastic tissues has been associated with tumor resistance to alkylating agents. The purposes of this study are to assay MGMT activity in ovarian cancers and to correlate MGMT titers with chemotherapy response to cisplatin and cyclophosphamide in patients with ovarian cancer. MGMT levels were determined by a biochemical assay of tumor tissues from 20 patients with ovarian malignancy. The clinical stages of the patients studied were 4 in Stage I, 2 in Stage II, 12 in Stage III, and 2 in Stage IV. The mean MGMT activity was 34 +/- 9 fmole methyls transferred/mg protein. Among 13 patients with tumor MGMT levels more than 10 fmole/mg protein, 10 (77%) of them were resistant to postoperative combination chemotherapy. In the remaining 7 patients with low MGMT titer of less than 10 fmole/mg protein, a majority (71%) had a complete response (P < 0.10). These preliminary results indicate that ovarian cancer has detectable MGMT activity, and this activity is possibly correlated with treatment failure to a postoperative cisplatin regimen.

Taxol in ovarian cancer.

Taxol is a structurally complex natural plant product with a novel mechanism of action. The supply of this drug is limited by its low abundance in the bark of the slow-growing yew tree from which it is extracted. The chemical complexity of taxol has hampered the development of a feasible process to synthesize large quantities. Analogues are being made from a precursor found in the needles of the yew tree. However, there is a need to develop a more efficient method to provide adequate supplies of this drug. This review article summarizes the preclinical and clinical studies of taxol in ovarian cancer. Phase I studies have identified the drug's toxicities. Neutropenia has been the dose-limiting toxicity in most trials, and premedications and longer infusion schedules have been used to reduce the incidence and severity of hypersensitivity reactions. The intraperitoneal administration of taxol in Phase I studies showed a pharmacologic advantage with acceptable toxicity. Its activity in ovarian cancer was noticed first in Phase I trials at the Albert Einstein College of Medicine and Johns Hopkins University. These observations led to Phase II testing, which documented response rates of 20-35% in patients with relapsed or refractory ovarian cancer. Phase III trials of taxol and cisplatin versus cyclophosphamide and cisplatin in untreated patients with ovarian cancer are in progress. Studies combining taxol with colony-stimulating factors and cisplatin are ongoing. Taxol is an important new drug in ovarian cancer. Its unique mechanism of action and toxicities make it an attractive agent to use in combination with currently active drugs. Future studies will determine the role of taxol in the management of this disease, but the widespread availability of this drug will depend on the development of a feasible synthetic process.