Search PubMed⌕ Search

Biomedical subjects

Claire F Verschraegen

Publications and source records attributed to Claire F Verschraegen.

At least 19 recordsLinked to original sources
PubMed2006

Incidence and survival rates for female malignant germ cell tumors.

OBJECTIVE: To evaluate 30-year, population-based trends in incidence and survival rates for malignant germ cell tumors originating within the female genital tract. METHODS: Surveillance, Epidemiology, and End Results data were used to identify malignant germ cell tumors (1973-2002). Overall and 5-year incidence rates, estimated annual percentage change, and survival rates were calculated and compared by age at diagnosis, race, stage, and histology. RESULTS: Of 1,262 cases, there were 414 (32.8%) dysgerminomas, 449 (35.6%) immature teratomas, 37 (2.9%) mature teratomas with malignant degeneration, and 362 (28.7%) mixed germ cell tumors. The 30-year, age-adjusted incidence rate per 100,000 women-years was 0.338, decreasing by 29.4% for dysgerminomas (P = .18) and by 31.5% for mixed germ cell tumors (P = .22). Other nonwhites had higher rates than whites and blacks, but dysgerminoma rates were higher in whites and other nonwhites than in blacks. Using the registries for expanded races, rates were higher for Asian/Pacific Islanders (P = .059) and Hispanics (P = .07). By age at diagnosis, 15-19 year olds had the highest rates and the only significant change in rates (37.5% increase, P = .008). The 5-year relative survival was 83.9%. Survival rates improved significantly over calendar time and varied by histologic subtype, race, stage of disease, and age at diagnosis. CONCLUSION: Over the past 30 years, germ cell tumor incidence rates have declined in women and differ from rising trends reported for testicular tumors. Survival rates have improved but were lower for older women and for nondysgerminoma subtypes.

Adolescent↗
PubMed2006

Changing trends in gestational trophoblastic disease.

OBJECTIVE: The New Mexico Tumor Registry (NMTR) and Surveillance, Epidemiology and End Results (SEER) registries were utilized to determine (30+)-year trends in gestational trophoblastic disease and choriocarcinoma. STUDY DESIGN: Age-adjusted incidence rates of gestational trophoblastic disease per 100,000 woman-years (1973-2003) and ratios per live births and pregnancies were calculated using data abstracted from the NMTR and state vital records. SEER data (1973-2002) were used to calculate age-adjusted incidence rates, estimated annual percentage change (EAPC) and relative survival rates for choriocarcinoma. RESULTS: In New Mexico there were 1,153 cases affecting 377 non-Hispanic whites, 504 Hispanics and 241 American Indians, with respective incidence rates of 3.494, 5.150 and 9.991 (p < 0.0001). American Indian incidence rates decreased 53.3%, from 13.34 (1988-1992) to 6.23 (1998-2002). Within SEER (1973-2002), there were 504 gestational choriocarcinomas. The 30-year incidence rate was 0.132 and decreased by 37.7% (EAPC, -2.1% per year; p=0.0001)-by 40.1% for whites, 55.9% for blacks and 62.1% for others. However, over the previous 10 years, rates among blacks (0.097 vs. 0.259, p = 0.01) and for distant disease (0.044 vs. 0.071, p = 0.046) increased. CONCLUSION: Disparities in incidence rates by race/ethnicity in New Mexico are decreasing. An increase in rates among blacks and distant disease diagnosis may be the consequence of fewer regional trophoblastic centers in the United States.

Adolescent↗
PubMed2005

Malignant adnexal masses in pregnancy.

Ovarian tumors during pregnancy are very rare; however, a cancer diagnosis causes distress to the couple. Reassurance is paramount, and the first consideration should be given to the safety of the mother. If both mother and fetus can be preserved, treatment to minimize the risks to both should be planned accordingly. It is imperative to care for the patient with a multidisciplinary team that includes a high-risk obstetrician, a gynecologic oncologist, and a medical oncologist specialized in gynecologic cancers.

Carcinosarcoma↗
PubMed2005

Alternative administration of camptothecin analogues.

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.

Administration, Cutaneous↗
PubMed2005

Frequent overexpression of STK15/Aurora-A/BTAK and chromosomal instability in tumorigenic cell cultures derived from human ovarian cancer.

The STK15 (also known as Aurora-A/BTAK) gene localized on chromosome 20q13 and encoding a centrosome-associated serine/threonine kinase is amplified and overexpressed in multiple human tumor cell types. Overexpression of this gene is involved in tumorigenic transformation, induction of centrosome duplication-distribution abnormalities, and aneuploidy in mammalian cells. To examine the potential role of STK15 in ovarian tumorigenesis, its mRNA and protein expression status were examined in cells grown in culture from 15 ovarian cancer specimens using semiquantitative RT-PCR and Western blot analysis. Normal ovarian surface tissues and the near diploid nontumorigenic breast epithelial cell line MCF10 were used as controls. The status of STK15 correlated with transformation-associated cellular phenotypes including tumorigenicity in nude mice, p53 expression level, and chromosomal ploidy. For chromosome ploidy analyses, FISH was carried out with direct fluorescence-labeled a-satellite probes for chromosome 3 and 17. STK15 mRNA was found overexpressed in 10 of the 15 ovarian cancer cell cultures. Five of these cell cultures revealed a truncated form of the STK15 protein with a molecular mass of 36 kDa. When tested for tumorigenicity in nude mice, 9 of the 10 cell cultures that overexpressed STK15 mRNA formed tumors in nude mice, while only one of the five cell cultures with no overexpression did. Cells overexpressing STK15 mRNA showed significant correlation with chromosome 3 polysomy. Six of the 13 (46%) cell cultures analyzed for p53 expression revealed overexpression of p53 and five of these six (83%) also overexpressed STK15. Four of the remaining seven cultures (57%) with overexpression of STK15 revealed minimal or no expression of p53. These results demonstrate that overexpression of STK15 significantly correlates with nude mice tumorigenicity and chromosomal aneuploidy in human ovarian cancer cells grown in vitro. Additionally, cells overexpressing STK15 also revealed frequent coordinate loss of wild-type p53 function manifested either as highly expressed intense staining reflective of a mutant form of p53 or almost complete absence of p53 staining. Overexpression of STK15 with coordinate loss of wild-type p53 function thus appears to play an important role in ovarian tumorigenesis and offers a novel molecular target in designing effective therapy of human ovarian cancer.

Aneuploidy↗
PubMed2004

Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(s)-camptothecin in patients with advanced pulmonary malignancies.

PURPOSE: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. EXPERIMENTAL DESIGN: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 micro g/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. RESULTS: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 micro g/kg/day. At 20.0 micro g/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. CONCLUSIONS: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient's plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 micro g/kg/day (equivalent to 0.5 mg/m(2)/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.

Administration, Inhalation↗
PubMed2004

Gestational trophoblastic neoplasia in American Indians.

OBJECTIVE: To analyze gestational trophoblastic neoplasia (GTN) trends among American Indians (AI) using population-based data. STUDY DESIGN: GTN incidence, by race and age, was calculated using data collected by the New Mexico Tumor Registry over 29 years (1973-2001). Live birth, pregnancy and women at risk were tabulated using data derived from the state's vital record annual reports and from the registry. Statistical methods included trends analysis and Poisson regression. There is no national registry in the United States for all GTN. Therefore, the Surveillance, Epidemiology and End Results (SEER) database was used to identify choriocarcinoma cases in American Indians between 1973 and 1999. RESULTS: Within New Mexico, 1,082 cases of GTN were identified among 752,374 live births and 904,831 pregnancies, with ratios of 1:695 and 1:836, respectively, affecting 234 AI, 355 non-Hispanic whites (NHW), 463 Hispanic whites (HW) and 30 other nonwhites. Ratios per live births (pregnancy), respectively, were significantly higher in AI (AI 1:439 [1:487], NHW 1:739 [1:949], HW 1:783 [1:903]), as was age-adjusted incidence per 100,000 woman-years (AI 10.62, NHW 3.53, HW 5.15; all P<.0001). Using Poisson models with live birth and woman-year denominators, AI were found to be at increased risk for all GTN histologic subsets (complete, partial and invasive hydatidiform mole and choriocarcinoma). Of 524 total gestational choriocarcinoma cases identified within SEER, 8 (1.8%) affected American Indians; of them, 7 were from New Mexico. CONCLUSION: In New Mexico, AI continue to be at higher risk of GTN than are other groups. Given the rarity of choriocarcinoma within SEER, especially among AI, the New Mexico dataset provides the best available estimate of trends in U.S. AI GTN risk.

Black or African American↗
PubMed2004

TLK-286.

Telik Inc is developing TLK-286, a modified glutathione analog prodrug, for the potential treatment of cancer.

Animals↗
PubMed2003

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan.

BACKGROUND: DX-8951f is a water-soluble camptothecin derivative with greater in vivo and in vitro activity than topotecan or irinotecan. The objectives of this phase II study were to determine the antitumor activity, safety and pharmacokinetic profile of DX-8951f administered intravenously for five consecutive days, every 3 weeks in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. METHODS: Enrolled in the study at The University of Texas M. D. Anderson Cancer Center were 16 patients with measurable cancer resistant to platinum, taxane and topotecan. All 16 patients were assessable for safety and 15 for efficacy analyses. Treatment consisted of a daily infusion of DX-8951f at 0.3 mg/m(2) per day (except for one minimally pretreated patient who started at 0.5 mg/m(2) per day) over 30 min for five consecutive days every 3 weeks. The pharmacokinetic and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Disease was stable in 7 of 16 patients (44%) (4 minor response and 3 stable disease). The median time to tumor progression was 43 days (95% CI 37-92 days). The median overall survival was 117 days (95% CI 90-279 days). The main toxic effect was neutropenia and leukopenia with 50% of patients experiencing grade 3 or 4 neutropenia and leukopenia. One episode of neutropenic fever was observed. Grade 3 or more anemia and thrombocytopenia were seen in 25% and 13% of patients, respectively. Grade 3 nonhematologic side effects included nausea (25% of patients) and fatigue (19%). Other side effects were not more than grade 2, and included gastrointestinal dysfunction, stomatitis, dermatitis, alopecia, liver dysfunction and drug fever. DX-8951 displayed linear pharmacokinetic characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were 2.1 l/h per m(2), 20 l/m(2) and 9.5 h, respectively. CONCLUSIONS: DX-8951f administered parenterally as a single agent daily at a dose of either 0.5 or 0.3 mg/m(2) per day for 5 days is feasible in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Although no responses were observed, a significant number of patients had stable disease with a decrease in CA-125 levels. In this heavily pretreated population, DX-8951f has clinically relevant hematologic and gastrointestinal toxicities in about 25% of patients. DX-8951 appeared to have linear pharmacokinetic characteristics on the basis of multiple administrations.

Adult↗
PubMed2003

Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl transferase inhibitor.

Farnesyl transferase inhibitors (FTIs) are novel antitumor drugs with clinical activity. FTIs inhibit cell growth not only by preventing direct Ras farnesylation but also through a Ras-independent pathway. Proteomics has been shown to be a powerful tool to monitor and analyze molecular networks and fluxes within the living cells and to identify the proteins that participate in these networks upon perturbation of the cellular environment. To observe early and dynamic protein changes in the cellular response to FTI in ovarian cancer cells, total proteins were extracted from 2774 cells treated or not with 10 microM manumycin, an FTI, for 3, 6 and 16 h. The proteins in the cells that were differentially expressed following treatment with manumycin for 3, 6 and 16 h were noted by two-dimensional electrophoresis and further identified by peptide mass fingerprinting as stress proteins. Both heat shock protein 70 (HSP70) and altered HSP70 were significantly up-regulated as early as 16 h in 2774 cells after exposure to manumycin. Since HSP70 plays an important role in protecting cells under stress, we treated the 2774 cells with the HSP inhibitor quercetin in combination with FTI. Quercetin dramatically enhanced the manumycin-mediated apoptosis in 2774 cells. Inducible HSP70 by manumycin in surviving ovarian cancer cells was also inhibited by quercetin as demonstrated by enzyme-linked immunosorbent assay. The inhibition of HSP70 by quercetin was correlated with enhancement of manumycin-induced mediated apoptosis in 2774 cells. The inhibition of HSP70 by 50 microM quercetin was also correlated with a decreased expression of procaspase-3 and enhancement of specific cleavage of poly (ADP-ribose) polymerase into apoptotic fragment in 2774 cells treated with manumycin. The interaction between the HSP70 inhibitor and FTI confirms the functional significance of the up-regulation of HSP70 as a protective mechanism against FTI-induced apoptosis and provides the framework for combination treatment of ovarian cancer.

Alkyl and Aryl Transferases↗
PubMed2003

Phase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer.

OBJECTIVE: The goal of this work was to study the anticancer activity of cetrorelix, a decapeptide with LHRH receptor antagonist properties in patients with platinum-resistant ovarian cancer. About 80% of primary ovarian cancers and cell lines bear LHRH receptors. Cetrorelix has anticancer activity in in vitro and in vivo ovarian cancer models. METHODS: Eligible patients with ovarian or mullerian carcinoma resistant to platinum chemotherapy received cetrorelix 10 mg subcutaneously every day. Eligibility criteria included age > or = 18, PS < or = 2, measurable disease, chemistries and blood counts in normal range, no estrogen replacement for at least 2 weeks, and no known allergic reactions to extrinsic peptide. In patients volunteering for a biopsy, tissue was taken to perform a LHRH receptor assay. RESULTS: Seventeen patients were treated. Median age was 58 years. Median performance status was 0. Median number of prior chemotherapies was 3. Three patients had partial remissions lasting 9, 16, and 17 weeks. Toxicities effects included grade 4 anaphylactoid reaction (one patient) controlled by cortisol and cimetidine, grade 2 histamine reaction (two patients), grade 2 arthralgia (one patient) 20% cholesterol increase (two patients, who did not require specific treatment), minor hot flushes, headache, and local skin reaction at the injection site. Six of seven samples were LHRH receptor positive for mRNA and/or ligand assay. Two responding patients were LHRH receptor positive. The patient who had no receptor did not respond. CONCLUSION: Cetrorelix has activity against ovarian cancer in this refractory population, and has minimal toxicity, except for potential anaphylactoid reactions. Activity may be mediated through the LHRH receptor.

Aged↗
PubMed2003

Cisplatin and irinotecan (CPT-11) for peritoneal mesothelioma.

Peritoneal mesothelioma is a rare malignancy that is seen in patients exposed to asbestos or in young women with no known exposure to asbestos. The clinical features of the disease are similar in these two groups, and include peritoneal carcinomatosis, ascites, thrombocytemia, systemic symptoms (fever and night sweats), and hypercoagulability. There is no known curative therapy for this disease. Cisplatin has activity in 25% of patients. Mesothelial cells are known to contain high levels of carboxylesterase, a key enzyme in the activation of Irinotecan (CPT-11) to SN-38. This retrospective review of our experience in combining cisplatin 50 or 60 mg/m2 i.v. or i.p. on day 1 with CPT-11 50 or 60 mg/m2 i.v. on day 1, 8, and 15. Courses were repeated every 4 weeks x 6. If i.p. administration of cisplatin were feasible, it was the preferred route. Response to treatment was based on RECIST criteria. Fourteen men and 3 women, median age 62 years (35-76 years) and median PS 1 (0-2) were treated. Median number of courses was two for nonresponders and six for responders. The overall response rate was 24%, but 76% of patients improved on treatment. Median survival is not reached. Grade > or = 2 side effects included anemia (n = 6), neutropenia (n = 3), nausea/vomiting (n = 4), and constipation (n = 2). Grade 1 side effects were fatigue, anorexia, weight loss, alopecia, diarrhea, neuropathy, and gastric reflux. There were no grade > or = 3 hematologic toxicities. The combination of cisplatin and CPT-11 is well tolerated and has clinical benefits in patients with peritoneal mesothelioma.

Adult↗
PubMed2003

Establishment and characterization of cancer cell cultures and xenografts derived from primary or metastatic Mullerian cancers.

PURPOSE: The purpose of this study was to characterize cell cultures and xenografts derived from patients with ovarian cancer. EXPERIMENTAL DESIGN: Ninety specimens from 67 patients were plated in RPMI 1640 or inoculated in nude mice. Growth characteristics of cell cultures and xenografts were determined. Expression of receptors for estrogen, progesterone, androgen, epithelial growth factor, fibroblast growth factor, HER-2/erbB-2/c-neu proto-oncogene, and the P53 expression were characterized by immunocytochemistry in 28 cell cultures. RESULTS: Forty-nine percent of samples were cultured successfully in vitro. Ascitic and pleural effusion specimens were more likely to produce a cell culture or a xenograft than solid tissue specimens (P < 0.005). All of the cell cultures had an epithelial morphology, and 89% were aneuploid with a mean DNA index of 1.6 (range, 0.9-3.0). Of 54 and 61 specimens inoculated into nude mice i.p. and s.c., 15 (28%) and 18 (30%) produced a xenograft, respectively, with two-thirds of these xenografts being reproducibly tumorigenic. The median time to first passage was 21 weeks for cell cultures and 8-12 weeks for xenografts. Expression of epithelial growth factor receptor, HER-2/erbB-2/c-neu proto-oncogene, fibroblast growth factor receptor, estrogen, progesterone, and androgen was seen in 24, 21, 31, 17, 43, and 18%, respectively. P53 was overexpressed in 62% of cell cultures analyzed. CONCLUSIONS: Ovarian cancer cells collected from effusions are easier to grow in vitro than in vivo. The only characteristic that may be associated with tumorigenicity was abnormal P53 expression. This panel of ovarian cancer materials provides useful models for biological or therapeutical studies.

Animals↗
PubMed2002

Safety and efficacy of transfusions of autologous cryopreserved platelets derived from recombinant human thrombopoietin to support chemotherapy-associated severe thrombocytopenia: a randomised cross-over study.

BACKGROUND: The increasing demand for platelet products, and concern over the transfusion-associated risks of alloimmunisation and infections, have motivated a search for improved methods aimed at keeping exposure to donor antigens to a minimum. Transfusion of thrombopoietin-derived autologous platelets might provide an alternative strategy. We aimed to compare the safety and efficacy of this strategy with that of transfusion with fresh allogeneic platelets in patients with severe chemotherapy-induced thrombocytopenia. METHODS: 20 patients with gynaecological malignancies were treated with two doses of 1.2 microg/kg recombinant human thrombopoietin. From day 12, we aimed to collect 50 units of platelets from these patients by plateletpheresis. Harvested platelets were cryopreserved in ThromboSol and 2% dimethyl sulfoxide (DMSO) for use in subsequent autologous transfusions. Patients then received carboplatin for up to six cycles. Patients were randomly assigned to group A (n=10), which received allogeneic fresh platelets at the first instance of severe thrombocytopenia (platelet count <15,000/microL) and then autologous cryopreserved platelets at the next, or to group B (n=10), which received first autologous and then allogeneic platelets. In subsequent cycles, all patients received autologous platelets while available. The primary endpoint was platelet count increment corrected for the number of platelets transfused and the patients' body-surface area. Analysis was by intention to treat. FINDINGS: Treatment with recombinant human thrombopoietin significantly increased platelet count (median 2.3-fold [range 1.5-3.3], p<0.0001) in all but one patient in group A. The median number of platelets collected per patient was 53 units (14-66) in two collections (one to three). There was no significant difference in the corrected platelet count increments (CCIs) between the 19 paired transfusions of cryopreserved autologous platelets and fresh allogeneic platelets (median 1-h CCI 15.7 vs 19.8, p=0.398; median 24-h CCI 13.0 vs 18.1, p=0.398). 14 of the 19 patients had a good response (1-h CCI >7.5) to their first transfusion of allogeneic platelets. By contrast, all patients had a good response to their first transfusion of autologous platelets (p=0.063). Moreover, no significant decrease in the CCIs (p=0.405) was seen over six cycles after autologous platelet transfusions (n=63). No transfusion reactions or any serious adverse event was recorded during autologous platelet transfusions. INTERPRETATION: Recombinant human thrombopoietin facilitated collection of multiple units of platelets, which could be cryopreserved and reinfused to counteract severe thrombocytopenia during multicycle chemotherapy. Transfusion of autologous cryopreserved platelets derived from recombinant human thrombopoietin can provide a viable strategy to minimise the risks of allogeneic platelet transfusions and provide a long-lasting supply of platelet support.

Adult↗
PubMed2002

Irinotecan for the treatment of cervical cancer.

Topoisomerase inhibitors have been widely studied for the treatment of refractory or recurrent cervical cancer. Various schedules have been used, with response rates ranging from 13% to 20%. The combination of cisplatin and irinotecan (CPT-11, Camptosar) is being studied in cervical cancer. Hematologic and gastrointestinal toxicities have been observed. Gastrointestinal toxicities have been particularly problematic at high irinotecan doses. Further studies of irinotecan in combination with other drugs and radiotherapy are warranted.

Antineoplastic Agents, Phytogenic↗
PubMed2002

KW-2170 (Kyowa Hakko Kogyo).

The pyrazoloacridone, KW-2170, an alkylating agent and topoisomerase II inhibitor, is being developed by Kyowa Hakko Kogyo as a potential treatment for cancer [273964], [409111], [422561]. By December 2001, KW-2170 had entered phase II trials in the US, following approval for the trial from the FDA, which was received in November 2001. At this time, the company planned to extend the phase II trials to Australia, Singapore, Taiwan and Costa Rica using data from US phase I trials. Accelerated Japanese trials were also planned, and an NDA was anticipated for 2006, with non-small-cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer and breast cancer as the targets [434794], [444539]. By August 2002, Japanese phase I trials had been completed [460177].

Journal Article↗
PubMedDate not supplied

Increased expression of heat shock protein 70 in adherent ovarian cancer and mesothelioma following treatment with manumycin, a farnesyl transferase inhibitor.

Since farnesylation by farnesyltransferase (FTase) is the first obligatory step in the signaling transduction pathway of ras p21, FTase has been the target of new anticancer treatment modalities. Famesyl transferase inhibitors (FTIs), a novel class of antitumor drugs that blocks the oncogenic activity of ras, were first developed as therapy for ras-mutated human tumors. FTIs are also capable of inhibiting tumors without ras mutations, while different mechanisms of cell growth inhibition by FTI have been proposed. In cell culture and in animal models, FTIs have been shown to be potent inhibitors of cancer cell growth. We showed that manumycin, a farnesyl pyrophosphate competitive inhibitor, inhibits ovarian and mesothelioma cancer cell growth. To examine the molecular changes after exposure to manumycin, total proteins from treated and untreated 2774 cell line were extracted and separated by two dimensional gel electrophoresis (2-DE) and detected by colloidal coomassie blue staining. The 2-DE was found reliable for comparison of protein profiles before and after manumycin treatment. Two protein spots (spot 1 and 2) appeared after manumycin treatment. Generated peptide peaks were matched by database query (prowl.rockefeller.edu/cgi-bin/ProFound) to a heat shock protein (HSP) and a modified HSP, both with MW 70 KD. The expression status of HSP 70 was confirmed by Western blot and HSP 70 ELISA using an antibody against HSP 70. The expression of HSP70 increased with the length of exposure to, and the dose of manumycin as demonstrated by ELISA. Increase in HSP70 expression was also observed by Western blot after a 48-hour treatment with manumycin in ovarian cancer cell line OVCAR3 and three other cell cultures derived from samples of patients diagnosed with ovarian cancer and mesothelioma. Our study is the first report demonstrating an up-regulation of HSP 70 in ovarian cancer cell lines and mesothelioma cell cultures after treatment with the FTI, manumycin. This up-regulation of HSP 70 may be a cellular mechanism of cell self-protection against the apoptotic process and cell death, and it may enhance resistance and account for the altered sensitivity of certain cancers to FTIs agents. HSPs may therefore be an important molecular target for drug intervention strategies.

Alkyl and Aryl Transferases↗