Biomedical subjects

K Y Look

Publications and source records attributed to K Y Look.

At least 37 records · Page 2Linked to original sources

PubMed1997

A phase II trial of amonafide in patients with nonsquamous cell carcinoma of the cervix. A Gynecologic Oncology Group study.

Twenty-seven patients with nonsquamous cell carcinoma of the cervix were entered into a Phase II study of amonatide; 24 patients were evaluable for toxicity, while 23 were evaluable for response. Patients received amonafide, 300 mg/m2, intravenously for 5 consecutive days every 3 weeks. The median age of patients was 45 years. All but two patients were completely ambulatory. Twelve patients had received prior chemotherapy, while 22 had been treated with radiation therapy. One of 27 (4.3%) patients had a partial response (PR) to this regimen and 13 (56.5%) had stable disease. Sixteen patients experienced a median white blood cell (WBC) nadir of 350/mm3, seven developed life-threatening thrombocytopenia, and one had severe anemia requiring transfusion. Nonhematologic toxicity was mild. Amonafide had insignificant activity in these patients with nonsquamous cell carcinoma of the cervix.

Adenine↗

PubMed1997

Comparison of combination therapy with paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with suboptimal stage III and stage IV ovarian cancer: a Gynecologic Oncology Group study.

This prospective study compared the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin with the standard therapy of cyclophosphamide/cisplatin in women with suboptimal stage III and stage IV ovarian cancer. Of the initial 410 women who presented with advanced disease and greater than 1 cm residual masses after initial surgery, 386 met all eligibility criteria and were randomly assigned to receive a regimen of cisplatin 75 mg/m2 and cyclophosphamide 750 mg/m2 or cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 delivered over 24 hours. Dosage reductions were permitted in the event of significant toxicity. Among 216 patients with measurable disease, responses were reported in 73% of those receiving cisplatin/paclitaxel and in 60% of those receiving cisplatin/cyclophosphamide. Median progression-free survival was significantly longer (P < .001) in the group treated with cisplatin/paclitaxel, compared with those receiving cisplatin/cyclophosphamide (17.9 v 12.9 months, respectively).

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.

BACKGROUND: Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. METHODS: We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over 24 hours). RESULTS: Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). CONCLUSIONS: Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.

Adult↗

PubMed1996

An atypical recurrence of endometrial carcinoma following estrogen replacement therapy.

Following an abdominal hysterectomy and bilateral salpin-goophorectomy wherein a superficial (1.6 mm) well-differentiated endometrial cancer and bilateral ovarian serous cystadenomas were discovered, estrogen replacement was given. One year later the patient presented with a 9 x 7-cm left groin recurrence. Patients with endometrial carcinoma may request estrogen replacement. The benefits of such replacement are well recognized; however, these patients also need to be counselled that hormonal replacement may be complicated by recurrence. Physicians need to be cognizant of symptoms or signs which would suggest disease recurrence at unusual sites in these patients who are perceived as being at low risk for recurrent disease.

Adenocarcinoma↗

PubMed1996

An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study.

The influence of cell type on recurrence-free interval (RFI) and survival after radical hysterectomy for patients with Stage IB carcinoma of the cervix was investigated. Patients with Stage IB carcinoma of the cervix (>3-mm invasion) underwent a radical hysterectomy and pelvic lymphadenectomy. Patients with involved paraaortic nodes or gross extracervical disease were excluded. Of 813 evaluable patients, 645 had squamous, 104 with adenocarcinoma, and 64 had adenosquamous cell type. The time to failure and the following clinical/pathologic characteristics were compared among the three cell types: age, Gynecologic Oncology Group performance status (PS), gross versus occult tumor, histologic grade, depth of invasion, node status, uterine extension, parametrial extension, surgical margins, and capillary-lymphatic space (CLS) involvement. A Cox proportional hazards model was used to compare the patients with adenosquamous and adenocarcinoma to those with squamous while adjusting for prognostic factors. The median age was 40 years (range, 21-87). Pelvic nodes were involved in 119 (15%) of patients. There were no significant differences between cell types in distributions of the following factors: age, PS, positive nodes, depth of invasion, uterine extension, surgical margins, or parametrial extension. There were statistically significant differences between cell types with regards to grade (P < 0.001), gross versus occult primary status (P = 0.016), and CLS involvement (P = 0.005). There was no statistically significant difference detected between cell types in crude comparisons of RFI (P = 0.29); however, there was a difference in survival (P = 0.02) with shorter survival seen in the adenosquamous cell type. After adjusting for CLS involvement, PS, depth of invasion, and clinical tumor size, survival remained worse for patients with adenosquamous primaries when compared to squamous carcinoma (P = 0.02) and adenocarcinoma (P = 0.007). In conclusion, no statistically significant differences were seen in RFI among cell types; however, in patients with Stage I carcinoma of the cervix overall survival after radical hysterectomy may be slightly worse for those with adenosquamous cell type.

Adenocarcinoma↗

PubMed1996

Current issues in the regulation of signal transduction.

(1) In all examined rat and human tissues and cells, PIP kinase activity was rate-limiting and PLC activity was present in great excess. (2) The steady-state activities of the signal transduction enzymes, PI kinase, PIP kinase and PLC, and the concentration of the end product, IP3, were determined in rat liver and hepatomas of different malignancies. The activities of all three enzymes were elevated in the hepatomas in a non-random fashion. A generalization emerged that the enzyme with the lowest activity in liver, PIP kinase, increased to the highest extent and the enzyme with the highest activity in liver, PLC, increased to the smallest extent in rapidly growing hepatomas. The IP3 concentration in the hepatomas was elevated in a progression-linked fashion. (3) The three signal transduction enzyme activities were elevated in human ovarian carcinoma samples and in human breast carcinoma cells. (4) When human breast carcinoma MDA-MB-435 cells were allowed to go through lag, log and plateau phases, the IP3 concentration reached a 20-fold peak at 12 hr after plating. The elevation in IP3 concentration preceded the rise in PI and PIP kinase activities which increased 11-fold in the log phase. The IP3 concentration and PI and PIP kinase activities returned to their baseline levels when the plateau phase was reached. The PLC activity did not change significantly during the whole period. (5) Administration of cycloheximide i.p. in rats revealed short half-lives in the bone marrow for the two kinases (8 min) and a long half-life for PLC (> 6 hr). In a group of 10 enzymes, the half-lives of the kinases were the shortest. In cycloheximide-injected rats, the bone marrow IP3 concentration was reduced to about 50% in 30 min. The reduction of IP3 concentration is attributed to the decline to 15 and 12%, respectively, in PI and PIP kinase activities since PLC activity did not change. (6) In 3-day starved rats, the bone marrow PI and PIP kinase were reduced to activities (13%) that were markedly lower than the decrease in the protein concentration (to 55%). By contrast, the PLC activity was preferentially maintained (to 78%) over the protein level. Under starvation, the IP3 concentration decreased (to 24%), indicating that starvation can markedly disrupt IP3 homeostasis. Refeeding returned the enzymic activities and the IP3 concentration to the normal level in bone marrow in 24 hr. (7) Comparison of the absolute activities of PI and PIP kinases and PLC showed that PLC is present in an excess; therefore, it does not appear to have a rate-limiting action in cycloheximide treated rats or in starvation. (8) Whereas PI and PIP kinases have short half-lives and apparently rapid synthetic rates, PLC has high activity, a long half-life and responds to starvation with only a small decrease. (9) The gain in function manifested in the over-expressed capacity for signal transduction confers growth advantages to cancer cells. These increased activities, particularly those of PI and PIP kinases, should be sensitive targets for chemotherapy.

Animals↗

PubMed1996

A phase II trial of merbarone (NSC 336628) in the treatment of recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study.

BACKGROUND: Patients with recurrent epithelial ovarian carcinoma who progress through a cisplatin-based regimen or recur less than 6 months after discontinuing cisplatin, have limited therapeutic options. The Gynecologic Oncology Group conducted a Phase II trial of merbarone in this patient population. METHODS: Twenty-seven patients with recurrent epithelial ovarian carcinoma who had previously received one prior cisplatin-based regimen were scheduled to receive 1000 mg/m2 of merbarone by continuous intravenous infusion through a central line each day for five days every four weeks. RESULTS: Of the 27 patients entered, one was ineligible because of wrong primary, and two never received the drug, leaving 24 patients evaluable for toxicity. Twenty of 24 were evaluable for response. The regimen was well tolerated with only one episode each of GOG grade 3 leukopenia (4%) or grade 4 granulocytopenia (4%). There was one episode (4%) of GOG grade 3 gastrointestinal toxicity. Prior to increasing the infusate concentration to 4 mg/ml, there was one episode (4%) of altered mental status which, in retrospect, may have been secondary to iatrogenic hyponatremia. There were two partial responses (10%) (95% confidence interval 1.2-31.7%). CONCLUSIONS: Merbarone exhibited minimal activity at this schedule in this pretreated group of patients with epithelial ovarian carcinoma.

Adult↗

PubMed1996

A phase II trial of didemnin B (NSC #335319) in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.

Didemnin B (NSC #335319) was administered i.v. to 26 evaluable patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix at 6.3 mg/m(2) every 28 days until progression of disease. No patient had had prior cytotoxic therapy alone. Some patients (4) were exposed to radiation sensitizers. There was one complete responder (4.5%). Six patients had stable disease (27.3%) and 15 (68.2%) had increasing disease. The toxicities were significant, with 11 patients (42.3%) experiencing grade 3 or 4 adverse effects. Didemnin B, when used with this dose and schedule, has minimal activity in squamous cell carcinoma of the cervix.

Adult↗

PubMed1996

A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

The addition of leucovorin to 5-fluorouracil (5-FU) has been shown to improve the response rate in recurrent colon cancer. The combination of low-dose leucovorin and 5-FU was previously tested by the Gynecologic Oncology Group (GOG) and did not produce response rates greater than rates using 5-FU alone. From June 1990 to April 1992, 55 patients with unresectable recurrent squamous cervical cancer received high-dose leucovorin at 200 mg/m2 i.v. bolus, followed by 5-FU at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses. Subsequent courses were given every 5 weeks. The median number of courses delivered was two (range 1-15). Fifty patients were evaluable for toxicity and 45 for response. Prior radiotherapy had been given to 43 patients and prior chemotherapy to 38. The overall response rate was 8.8% (95% confidence interval, 2.5-21.2%). There were two complete responses (4.4%) and two partial responses (4.4%). One response was in the pelvis and three were outside the pelvis. None of the extrapelvic responses had received irradiation at the site of measurable disease. The major adverse effect was granulocytopenia, with 15/50 (30%) experiencing GOG grade 3 or 4 granulocytopenia. The median white blood count for patients experiencing leukopenia was 2,000 (range 400-3,800). Grade 3 or 4 gastrointestinal toxicity was seen in 12 patients (24%). In this pretreated population, patients receiving high-dose leucovorin with 5-FU had moderate toxicity but only minimal activity.

Antidotes↗

PubMed1996

Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group).

Administration of an alkylating agent plus a platinum coordination complex is standard therapy for advanced epithelial ovarian cancer in the United States. The most commonly used combination is cyclophosphamide/ cisplatin; however, the benefit of this combination in overall survival has not been compelling. We report a prospective comparison of this regimen versus a combination of cisplatin with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new and well-tolerated agent with documented activity in cisplatin-refractory ovarian cancer. Three hundred eighty-six patients with advanced ovarian cancer and greater than 1 cm residual masses following initial surgery were randomly assigned to receive a regimen of cisplatin (75 mg/m2) and cyclophosphamide (750 mg/m2), or cisplatin (75 mg/m2) and paclitaxel (135 mg/m2), delivered over 24 hours. Dose reductions in cyclophosphamide or paclitaxel were permitted for significant toxicity. In 216 patients with measurable disease, responses were reported in 73% of those randomized to the cisplatin/paclitaxel arm and in 60% randomized to the cisplatin/cyclophosphamide arm. Progression-free survival was significantly longer (P < .001) with cisplatin/paclitaxel (median, 12.9 v 17.9 months). Overall survival was also significantly longer (P < .001) with cisplatin/paclitaxel (median, 37.5 v 24.4 months). Incorporating paclitaxel into first-line therapy for patients with suboptimally debulked stage III and stage IV ovarian cancer can increase the duration of the progression-free interval and extend overall survival while maintaining an acceptable toxicity profile.

Adult↗

PubMed1995

The fate of the ovaries after radical hysterectomy and ovarian transposition.

To assess the effectiveness of lateral ovarian transposition in preserving normal ovarian function, the medical records of 200 consecutive women with stage I-IIA cervical cancer treated primarily with radical hysterectomy and pelvic lymphadenectomy were reviewed. Lateral ovarian transposition was performed at the time of radical hysterectomy in 132 (66%) patients and 28 (21%) received postoperative pelvic radiation therapy. Menopausal symptoms (vaginal dryness, hot flushes) and follicle-stimulating hormone (FSH) levels were used to define ovarian function. Only 3/104 (2.9%) patients who underwent lateral ovarian transposition without postoperative pelvic radiotherapy experienced menopausal symptoms; however, FSH levels in all three cases suggested continued ovarian function. In 14/28 (50%) patients who received postoperative pelvic radiation therapy ovarian failure occurred. The risk of ovarian failure with pelvic radiation therapy after lateral ovarian transposition was significant (RR = 17.3; 95% CI = 5.35-56.13). The incidence of adnexal disease in transposed ovaries requiring analgesics or further surgery was 3%. These data suggest minimal risk to the patient when the ovaries are conserved. Unfortunately, lateral ovarian transposition preserves ovarian function in only 50% of patients undergoing pelvic radiotherapy following radical hysterectomy.

Adult↗

PubMed1995

Pelvic exenteration for malignant melanomas of the vagina or urethra with over 3 mm of invasion.

Pelvic exenteration has usually been employed as salvage treatment for gynecologic malignancies which have failed primary radiotherapy. The therapeutic mainstay for vulvar melanomas has become wide local excision with or without concurrent regional node dissection. Patients with primary melanoma of the vagina who undergo exenteration as primary therapy may experience 50% 5-year survival if the pelvic nodes are free of metastases. However, the overall 5-year survival for vaginal melanoma is 15%. In our patient population, there have been four patients with vaginal or urethral melanomas treated primarily with pelvic exenteration. The purpose of this study was to report that patients with vaginal or urethral melanomas over 3 mm in thickness may benefit from primary pelvic exenteration. Four patients underwent pelvic exenteration at Indiana University Medical Center for malignant melanoma of the vagina or urethra between 1986 and 1992. The pathologic specimens of all patients were analyzed for thickness, growth pattern, and nodal metastases. Patient age ranged from 50 to 71. Thickness of the melanomas ranged from > 3 to 12 mm. All four patients underwent exenterations, three total and one anterior. All patients had negative pelvic and inguinal nodes at the time of surgery. None of the patients has experienced a recurrence. Three of four patients are alive without evidence of disease at 31 to 97 months following their exenteration. One patient died postoperatively of cardiopulmonary complications. Patients with melanomas of the vagina and female urethra, greater than 3 mm in thickness, may benefit from primary pelvic exenteration.

Aged↗

PubMed1995

Linkage of reduction in 1-phosphatidylinositol 4-kinase activity and inositol 1,4,5-trisphosphate concentration in human ovarian carcinoma cells treated with quercetin.

Quercetin inhibited 1-phosphatidylinositol (Pl) 4-kinase, EC 2.7.1.67 (Pl kinase) activity in a concentration-dependent manner (IC50 = 4 microM) in particulate extracts from human ovarian carcinoma. In OVCAR-5 cells quercetin produced growth inhibition (IC50 = 63 microM) and cytotoxicity (LC50 = 17 microM). The growth inhibition by quercetin was accompanied by an 80% decrease in Pl kinase activity and a 65% decrease in the concentration of the second messenger, inositol 1,4,5-trisphosphate (IP3). When human OVCAR-5 cells were plated and expressed their neoplastic proliferative program in the log phase, Pl kinase and Pl 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) activities coordinately increased to a peak of 5.8- and 4.5-fold, respectively. The results demonstrate for the first time inhibition by quercetin of the enhanced capacity for operation of signal transduction in human ovarian carcinoma cells, thus providing a novel target in cancer cells.

1-Phosphatidylinositol 4-Kinase↗

PubMed1995

Regulation of signal transduction.

1. A systematic study is reported on the control of 1-phosphatidylinositol 4-kinase (PI kinase) and PI 4-phosphate 5-kinase (PIP kinase), enzymes of the phosphatidylinositol phosphorylation pathway which leads to the production of second messengers. IP3 and DAG. In liver of normal male, adult, fed Wistar rats the steady state activity of PI kinase was 0.5 +/- 0.01 and that of PIP kinase was 0.046 +/- 0.003 nmol/hr/mg protein. The concentration of IP3 was 1.8 +/- 0.1 pmol/mg protein. 2. That the two kinases have short half-lives was observed in starvation. where in the rat liver or bone marrow activities rapidly decreased and on refeeding were restored in a day. Injection to rats of the protein synthetic inhibitor, cycloheximide, yielded t1/2 = 80 min for the two enzymes in bone marrow and t1/2 = 80 min in liver. 3. Linkage of the signal transduction enzymes with proliferation was shown by the high activities as compared to liver of these enzymes in rat organs of high cell renewal capacity, e.g., thymus, bone marrow, spleen and testes. 4. Linkage with malignant proliferation was indicated by the observation that in rat hepatomas the enzyme activities increased 5- to 9-fold and were highest in rapidly growing hepatoma 3924A (29- and 45-fold). 5. In human primary ovarian carcinoma PI and PIP kinase activities were elevated 4.4 and 2.9-fold, respectively, and in OVCAR-5 cells, 32- and 11-fold, respectively. Similar increases were observed in MDA-MB-435 human breast carcinoma cells in comparison with normal breast parenchymal cells. 6. The linkage of signal transduction enzyme activities with malignant proliferation was also observed in experiments when human breast carcinoma cells were plated in flasks and expressed their proliferative capacity in the log phase. PI and PIP kinase activities steadily and coordinately increased to a peak 11-fold rise in mid-log phase. In late log and plateau phases the kinase activities gradually declined to the starting level. Similar observations were made for the two enzymes in human ovarian carcinoma OVCAR-5 cells and in rat hepatoma 3924A cells in tissue culture. 7. In animals injected with cycloheximide the bone marrow PI and PIP kinase activities exhibited t1/2 = 0.12 hr, the shortest decay rate in comparison with 8 enzymes of purine and pyrimidine biosynthesis with t1/2 = 0.6 to 4.3 hr. 8. Injection of tiazofurin decreased PI and PIP kinase activities in the bone marrow with t1/2 = 82 and 78 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Phosphatidylinositol 4-Kinase↗

PubMed1995

A phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study.

In this series 49 patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy received leucovorin 200 mg/m2 i.v. bolus followed by 5-fluorouracil at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses and subsequent courses were given every 5 weeks. Of this group, 47 patients were evaluable for toxicity and 44 for response. Of the patients evaluable for response, 15 were considered platinum-sensitive and 29 were platinum-refractory. The overall response rate was 6/44 (13.6%). There were two complete responders (4.5%) and four partial responders (9.1%). In the platinum-sensitive patients, there was one complete response, yielding a response rate of 6.6%, whereas in the platinum-refractory patients, there were four partial responses and one complete response for a response rate of 17.2%. Five responses were in the pelvis and there was one response at an extrapelvic site in the abdominal mesentery. The median number of courses delivered was three (range: 1-10). The major adverse effect was myelosuppression with 16/47 (34.0%) experiencing granulocytopenia < 1,000/mm3. The median white blood count nadir for the patients experiencing any leukopenia was 2,700 (range: 400-3,900/mm3). There was one episode of grade 3 thrombocytopenia. Grade 3 intestinal toxicity was seen in seven patients (14.9%). There were no treatment-related deaths. In this previously treated population, 5-fluorouracil with high-dose leucovorin exhibited activity of interest in the platinum-refractory population and warrants further investigation.

Adult↗

PubMed1995

A phase II study of fazarabine in patients with advanced ovarian cancer. A Gynecologic Oncology Group study.

BACKGROUND: A total of 22 patients with recurrent ovarian cancer previously treated with cisplatin-containing chemotherapy were treated with Fazarabine. METHODS: The drug was administered at an initial dose of 30 mg/m2/day for 5 consecutive days. Cycles were repeated every 28 days. There were 19 evaluable patients. RESULTS: No complete or partial responders were observed in this study; 48% of patients were deemed to have stable disease. The major toxicity was hematologic, with four patients exhibiting grade 4 neutropenia. CONCLUSIONS: Fazarabine shows no useful activity as a single agent when given at this dose and schedule in the management of previously treated patients with cancer of the ovary.

Adenocarcinoma↗

PubMed1995

A phase II trial of merbarone (NSC 336628) as salvage therapy for squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.

Twenty-seven patients with previously irradiated unresectable recurrent squamous carcinoma of the cervix who had failed one prior cytotoxic regimen received 1,000 mg/m2 per day of merbarone given by continuous i.v. infusion for 5 days every 4 weeks through a central line. One patient was never treated, and four were inevaluable for response, leaving 26 patients evaluable for toxicity and 22 evaluable for response. The major adverse effect was myelosuppression with 6/26 (23%) experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 leukopenia. There were two episodes (3.8%) of GOG grade 3 SGOT elevation. There were two patients (9.0%) who developed mental status changes classified as grade 3 neurotoxicity. This neurotoxicity may have been secondary to iatrogenic hyponatremia caused by the large volumes of 5% glucose infusion required at the original infusate concentration. After the concentration of the merbarone infusate was increased to 4 mg/ml, no further problems with hyponatremic neurotoxicity were encountered. The overall response rate was 2/22 (9.0%) (95% confidence interval 1.1-29.2%). In this pretreated population with recurrent squamous cervical carcinoma, merbarone exhibited only minimal activity.

Adult↗

PubMed1994

Coordinated increase in activities of the signal transduction enzymes PI kinase and PIP kinase in human cancer cells.

The steady-state activities of the first two enzymes of the phosphatidylinositol (PI) phosphorylation pathway, PI 4-kinase, EC 2.7.1.67 (PI kinase) and PI 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) as compared to human normal ovary are elevated in human ovarian carcinomas (4.1- and 2.7-fold) and in human OVCAR-5 cells in tissue culture (31.2- and 8.9-fold). Compared to normal human breast parenchymal cells. PI kinase and PIP kinase activities were increased in breast carcinoma MDA-MB-435 cells grown in nude mice as solid tumors (7.3- and 2.3-fold, respectively) and in MDA-MB-435 cells grown in tissue culture (95.8- and 15.5-fold, respectively). When the human carcinoma cells were plated and expressed their neoplastic proliferative program in the log phase, in the MDA-MB-435 breast carcinoma cells the PI and PIP kinase activities coordinately increased 11-fold; in ovarian carcinoma OVCAR-5 cells 5.8- and 4.5-fold, respectively. These studies provide the first evidence in human cancer cells of an increased capacity for the operation of signal transduction. This is indicated by the markedly elevated activities of PI and PIP kinases in the phosphatidylinositol phosphorylation sequence which leads to production of second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

1-Phosphatidylinositol 4-Kinase↗