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Biomedical subjects

S Mani

Publications and source records attributed to S Mani.

At least 19 recordsLinked to original sources
PubMed2006

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone.

BACKGROUND: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. RESULTS: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050). CONCLUSIONS: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.

Adult↗
PubMed2006

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole.

Individual variation in drug metabolism is a major cause of unpredictable side effects during therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate expression of genes such as CYP (cytochrome)3A4 and MDR-1 (multi-drug resistance-1), that are involved in this process. We have found that xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, a commonly used antifungal drug. Ketoconazole mediated its effect by inhibiting the activation of NRs, human pregnenolone X receptor and constitutive androstene receptor, involved in regulation of CYP3A4 and MDR-1. The effect of ketoconazole was specific to the group of NRs that control xenobiotic metabolism. Ketoconazole disrupted the interaction of the xenobiotic receptor PXR with the co-activator steroid receptor co-activator-1. Ketoconazole treatment resulted in delayed metabolism of tribromoethanol anesthetic in mice, which was correlated to the inhibition of PXR activation and downmodulation of cyp3a11 and mdr-1 genes and proteins. These studies demonstrate for the first time that ketoconazole represses the coordinated activation of genes involved in drug metabolism, by blocking activation of a specific subset of NRs. Our results suggest that ketoconazole can be used as a pan-antagonist of NRs involved in xenobiotic metabolism in vivo, which may lead to novel strategies that improve drug effect and tolerance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors.

Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl)retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.

Animals↗
PubMed2005

Antisense strategies for oncogene inactivation.

Antisense oligonucleotides have been evaluated as antineoplastic agents in a series of clinical trials, with mixed results. However, phase III trials incorporating G3139, a phosphorothioate oligomer targeted to the initiation codon region of the bcl-2 mRNA, have recently been completed in advanced melanoma, myeloma, and chronic lymphocytic leukemia (CLL). This article discusses the mechanism of the antisense effect and its dependence on the cellular internalization of oligonucleotides and the activity of RNase H. It also describes the properties, specific and nonspecific, of phosphorothioate oligonucleotides, the predominant species in current clinical trials, and discusses pharmacokinetic data obtained from earlier phase I and II trials employing these molecules. While the application of antisense technology to the treatment of human cancer is conceptually straightforward, in practice there are many complicated, mechanistically based questions that must be considered.

Clinical Trials as Topic↗
PubMed2005

The evolving portrait of cancer metastasis.

The phenomenon of cancer metastasis remains poorly understood. We discuss here various conceptual frameworks that attempt to rationalize the mechanisms by which tumors acquire metastatic ability. Portrayal of cancer as a somatic Darwinian process occurring within a tissue fails to fully explain the phenomenon of metastatic competence. The biology of pre-neoplastic cells also complicates this picture, since the phenotypes of normal cellular precursors are clearly relevant to metastatic behavior following transformation. Recent experimental results help to shed light on these and other considerations regarding the molecular mechanisms of malignant progression.

Animals↗
PubMed2004

Ovarian function and morphology after deletion of the DARPP-32 gene in mice.

A plethora of systemic and local signaling molecules regulate ovarian function, but how different signaling molecules interact within an ovarian target cell is not known. Here we report that endocrine cells of the ovary express a phosphoprotein, DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), which integrates signaling molecules in neurons. We thus hypothesized that DARPP-32 might act in a similar way in ovarian endocrine cells and therefore studied whether DARPP-32 gene deletion has consequences for ovarian functions in mice. Reproductive performance of adult mutants did not differ from wild-type females, as judged from numbers of litters and pups delivered. Similar steroid levels in mutant and wild-type mice ruled out gross abnormalities in the hypothalamic-pituitary-ovarian axis. However, an analysis of ovarian morphology, using serially sectioned ovaries, revealed several differences. Ovaries of young adult mutant mice at 2 - 3 months contained luteinized follicles, but fewer corpora lutea. At 5 - 6 months, large cysts were found in mutant mice, as well as reduced numbers of preantral follicles and antral follicles. Interstitial cell hypertrophy and degeneration was marked in all mutant ovaries at this age. Thus, while the lack of DARPP-32 does not overtly alter reproductive performance in adult mice, it is associated with progressive alterations and derangements of growth and development of ovarian follicles, suggesting premature ovarian ageing. This implies that ovarian DARPP-32 is involved in follicular development, presumably by integrating effects of signaling molecules, which act together to ensure efficient follicular development.

Animals↗
PubMed2003

Phase II study of flavopiridol in patients with advanced colorectal cancer.

BACKGROUND: Flavopiridol, a synthetic flavone that inhibits cell cycle progression, has demonstrated activity in colon cancer in xenografts and in a phase I trial. We evaluated flavopiridol in a phase II trial in patients with previously untreated advanced colorectal cancer (ACRC). PATIENTS AND METHODS: Twenty chemotherapy-naïve patients with ACRC received flavopiridol at a dose of 50 mg/m(2)/day via a 72-h continuous infusion every 14 days. Response was assessed by computed tomography or magnetic resonance imaging every 8 weeks. RESULTS: Twenty patients were enrolled; 19 were evaluable for toxicity and 18 for response. There were no objective responses. Five patients had stable disease lasting a median of 7 weeks. The median time to progression was 8 weeks. Median survival was 65 weeks. The principal grade 3/4 toxicities were diarrhea, fatigue and hyperglycemia, occurring in 21%, 11% and 11% of patients, respectively. Other common toxicities included anemia, anorexia and nausea/vomiting. CONCLUSIONS: Flavopiridol in this dose and schedule does not have single-agent activity in patients with ACRC. Recent preclinical data suggest that flavopiridol enhances apoptosis when combined with chemotherapy. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC.

Adult↗
PubMed2003

Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). PATIENTS AND METHODS: Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m(2)/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450-650 mg/m(2). Oxaliplatin was administered on day 1 over 2 h at 85-130 mg/m(2). For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. RESULTS: Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.

Adult↗
PubMed2003

Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I.

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.

Antineoplastic Agents↗
PubMed2003

Signalling mechanisms in progesterone-neurotransmitter interactions.

The current and expanded view of transcriptional regulation by the steroid/thyroid superfamily of nuclear transcription factors integrates not only the hormone-dependent but also the hormone-independent cellular signaling mechanisms in physiology and reproduction. This effort has vastly been aided by the identification of steroid hormone receptors as transcriptional mediators of a variety of ligands, whose transcriptional response is dependent upon cross-talk with distinct signal transduction pathways, their recruitment of coregulators, alteration of chromatin structure and identification of specific interactive motifs within the receptors themselves. This review will provide a framework for the current concepts in the field of steroid hormone action as exemplified by our studies on progesterone receptor in female sexual behavior.

Animals↗
PubMed2001

Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS AND METHODS: Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m(2) (Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m(2) (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6-8 weeks. RESULTS: Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule 1 maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fluorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week when combined with 5-FU dosed at 200 mg/m(2)/day (Days 1-14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule 1 cycle 1, nonhematologic toxicity was common and included Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (1 patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (1 patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82-22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4-12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2-26.8%): 2 patients with 5-FU refractory colon carcinoma, 1 patient with hepatoma, 1 patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and 1 patient with cisplatin-resistant head and neck squamous cell carcinoma had a partial response. CONCLUSIONS: For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m(2) given as a continuous infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days 1 and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation.

Adult↗
PubMed2001

Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer.

PURPOSE: TAS-103 is an inhibitor of both topoisomerase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P <.05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P <.05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m(2), or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

Adult↗
PubMed2001

Histone acetylation and the cell-cycle in cancer.

A number of distinct surveillance systems are found in mammalian cells that have the capacity to interrupt normal cell-cycle progression. These are referred to as cell cycle check points. Surveillance systems activated by DNA damage act at three stages, one at the G1/S phase boundary, one that monitors progression through S phase and one at the G2/M boundary. The initiation of DNA synthesis and irrevocable progression through G1 phase represents an additional checkpoint when the cell commits to DNA synthesis. Transition through the cell cycle is regulated by a family of protein kinase holoenzymes, the cyclin-dependent kinases (Cdks), and their heterodimeric cyclin partner. Orderly progression through the cell-cycle checkpoints involves coordinated activation of the Cdks that, in the presence of an associated Cdk-activating kinase (CAK), phosphorylate target substrates including members of the "pocket protein" family. One of these, the product of the retinoblastoma susceptibility gene (the pRB protein), is phosphorylated sequentially by both cyclin D/Cdk4 complexes and cyclin E/Cdk2 kinases. Recent studies have identified important cross talk between the cell-cycle regulatory apparatus and proteins regulating histone acetylation. pRB binds both E2F proteins and histone deacetylase (HDAC) complexes. HDAC plays an important role in pRB tumor suppression function and transcriptional repression. Histones are required for accurate assembly of chromatin and the induction of histone gene expression is tightly coordinated. Recent studies have identified an important alternate substrate of cyclin E/Cdk2, NPAT (nuclear protein mapped to the ATM locus) which plays a critical role in promoting cell-cycle progression in the absence of pRB, and contributes to cell-cycle regulated histone gene expression. The acetylation of histones by a number of histone acetyl transferases (HATs) also plays an important role in coordinating gene expression and cell-cycle progression. Components of the cell-cycle regulatory apparatus are both regulated by HATs and bind directly to HATs. Finally transcription factors have been identified as substrate for HATs. Mutations of these transcription factors at their sites of acetylation has been associated with constitutive activity and enhanced cellular proliferation, suggesting an important role for acetylation in transcriptional repression as well as activation. Together these studies provide a working model in which the cell-cycle regulatory kinases phosphorylate and inactivate HDACs, coordinate histone gene expression and bind to histone acetylases themselves. The recent evidence for cross-talk between the cyclin-dependent kinases and histone gene expression on the one hand and cyclin-dependent regulation of histone acetylases on the other, suggests chemotherapeutics targeting histone acetylation may have complex and possibly complementary effects with agents targeting Cdks.

Acetylation↗
PubMed2001

Transcriptional activation by hepatocyte nuclear factor-4 in a cell-free system derived from rat liver nuclei.

Hepatocyte nuclear factor-4 (HNF4) regulates gene expression by binding to direct repeat motifs of the RG(G/T)TCA sequence separated by one nucleotide (DR1). In this study we demonstrate that endogenous HNF4 present in rat liver nuclear extracts, as well as purified recombinant HNF4, activates transcription from naked DNA templates containing multiple copies of the DR1 element linked to the adenovirus major late promoter. Recombinant HNF4 also activates transcription from the rat cellular retinol binding protein II (CRBPII) promoter in vitro. The region between -105 and -63 bp of this promoter is essential for HNF-mediated transactivation. The addition of a peptide containing the LXXLL motif abolished HNF4-mediated transactivation in vitro suggesting that LXXLL-containing protein factor(s) are involved in HNF4-mediated transactivation in rat liver nuclear extracts. This is the first report on transactivation by HNF4 in a cell-free system derived from rat liver nuclei.

Amino Acid Sequence↗
PubMed2001

Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations.

PURPOSE: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. PATIENTS AND METHODS: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. RESULTS: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m(2)/d to 16 mg/m(2)/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m(2)/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not correlate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m(2)/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 +/- 2.0 mL/min and 71.3 +/- 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m(2)/d. CONCLUSION: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.

Adult↗
PubMed2001

Ligand-independent activation of progestin receptors in sexual receptivity.

Ovarian steroid hormones, estradiol and progesterone, regulate cellular functions in the central nervous system, resulting in the alterations in physiology and reproductive behavior. One means by which steroid hormones exert their neural effects on reproductive behavior is via their intracellular receptors functioning as ligand-dependent transcription factors. Studies from our laboratory in the past few years have shown that in addition to their cognate ligands, neurotransmitters like dopamine can activate intracellular steroid receptors in a ligand-independent manner. Using biochemical and molecular approaches we have demonstrated that the effects of neurotransmitter dopamine, on reproductive behavior in female rats and mice, occur by means of cross talk between membrane receptors for dopamine and intracellular progestin receptors (PRs). In this article, our studies on the integration of intracellular signaling pathways leading to the activation of PRs and its impact on modulation of reproductive behavior are summarized.

Animals↗
PubMed2001

Failure to express GAP-43 during neurogenesis affects cell cycle regulation and differentiation of neural precursors and stimulates apoptosis of neurons.

GAP-43 is first expressed in proliferating neuroblasts and is required for maturation of neurons. When GAP-43 is not expressed in differentiating embryonal carcinoma P19 cells, reduced numbers of neurons were generated. Here we show that neuronal differentiation is initially disrupted at the onset of cell-cycle arrest in aggregated, proliferating neuronal precursors. The ratio of nestin:beta-tubulin-labeled progeny generated at this stage suggests that the differentiation is asymmetric. Apoptosis of immature neurons subsequently produced was also significantly induced. In vivo, too, proliferation of neuroblasts was significantly reduced in cortex of GAP-43(-/-) mice at E14.5. These data demonstrate that when GAP-43 is not expressed in proliferating neuroblasts, neural differentiation is not initiated appropriately, inducing apoptosis. Moreover, the concurrent inhibition of Ca2+-dependent adhesion between differentiating P19 cells in aggregates implicates GAP-43 in CAM-mediated signaling during neurogenesis, as has been previously shown in growth cones.

Animals↗