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PubMed1990

Apparent post-transcriptional modification of ornithine decarboxylase accounts for its induction in IEC-6 cells in culture.

Putrescine, the product of the ornithine decarboxylase (ODC)-catalyzed reaction, stimulates macromolecular synthesis in a duodenal crypt cell line, IEC-6 cells, grown in culture. In addition, supplementation of medium with putrescine alone reverses the inhibition of proliferation produced by inhibition of ODC with difluoromethylornithine (DFMO). A series of experiments was initiated in the IEC-6 cell line to study the regulation of induction of ODC, as this enzyme is rate-limiting in putrescine synthesis. Five percent fetal bovine serum (FBS) and 10 nM IGF-II stimulated a 21-fold and 6-fold induction of ODC activity, respectively. Kinetic analysis indicated that the effect was on the Vmax of the reaction and not on the Km, suggesting an increase in total ODC protein. This was verified by measuring [3H]DFMO binding; serum-stimulated induction of activity was accompanied by a corresponding 20-fold increase in the specific binding of DFMO to ODC. In contrast, Northern analysis demonstrated only a two-fold change in ODC mRNA level during induction. Measurement of enzyme stability showed that the half-life of the ODC protein was increased three-fold above basal level in the induced state. Inhibition of induction was produced by pretreatment with either the calmodulin antagonist, W-7, or the product of the ODC-catalyzed reaction, putrescine. Further analysis illustrated that the inhibition produced by these agents was partly the result of destabilization of the enzyme and not a decrease in message level. These results demonstrate that the induction of ODC by trophic agents is the result of post-transcriptional events rather than at the level of RNA synthesis.

Animals↗
PubMed2001

Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload.

BACKGROUND: Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function. METHODS AND RESULTS: To determine the mechanism of activation of MAPK pathways during the development of cardiac hypertrophy, we evaluated the induction of MAPK activity after aortic constriction in wild-type and in 2 types of cardiac gene-targeted mice: one overexpressing a carboxyl-terminal peptide of Galpha(q) that inhibits G(q)-mediated signaling (TG GqI mouse) and another overexpressing a carboxyl-terminal peptide of beta-adrenergic receptor kinase-1 that inhibits Gbetagamma signaling (TG betaARKct mouse). Wild-type mice with pressure overload showed an acute induction of JNK, followed by the induction of p38/p38beta at 3 days and ERK at 7 days. Both JNK and p38 activity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abolished, whereas the induction of p38 and p38beta was robust, but delayed. By contrast, all 3 MAPK pathways were activated by aortic constriction in the TG betaARKct hearts, suggesting a role for Galpha(q), but not Gbetagamma. CONCLUSIONS: Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of G(q)-coupled receptors and that non-G(q)-mediated pathways are recruited to activate p38 and p38beta.

Animals↗
PubMed1978

Enzyme induction by drugs. Its relevance to clinical biochemistry.

The properties of the hepatic microsomal, drug detoxicating, enzyme system are reviewed with particular reference to its inducibility. Induction is modified by various factors of which the diet is particularly important. A theoretical model system for induction has been proposed and this is discussed. There are a number of methods for assessing microsomal enzyme induction in man, none of which is ideal. Nevertheless, induction is a well recognized phenomenon in man and has a bearing on the metabolism of a number of endogenous substances. The effect of induction on steroid metabolism and the relationship between inducers, vitamin D, and metabolic bone disease is discussed. Bilirubin metabolism is affected by changes in microsomal enzyme activity and inducers have been used therapeutically in some cases of hyperbilirubinaemia. The relationship between drugs and the hepatic porphyrias is reviewed. The hepatic microsomal enzyme system is but one of many inducible enzymes and the role of induction in general in metabolic regulation is emphasised.

Animals↗
PubMed1992

Consolidation hemibody radiotherapy following induction combination chemotherapy in high-tumor-burden multiple myeloma.

PURPOSE: Curative therapy for multiple myeloma continues to be an elusive goal. This report discusses the Northern California Oncology Group (NCOG) phase I and II trial in high-tumor-burden disease that used a strategy that consisted of induction chemotherapy (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP]) for eight cycles followed by sequential hemibody radiation therapy (RT) and subsequent chemotherapy for an additional eight cycles. PATIENTS AND METHODS: Seventy-two previously untreated stage III myeloma patients were entered onto the study. Sixty-nine received induction chemotherapy, 40 received induction chemotherapy and hemibody RT, and 23 received induction chemotherapy, hemibody RT, and consolidative chemotherapy. RESULTS: Twenty-two complete responses (CRs) were obtained by induction chemotherapy, with four additional CRs after RT and consolidative chemotherapy. Nineteen patients developed grade 4 hematologic toxicity primarily after upper hemibody RT. Eight of these developed long-standing neutropenia or thrombocytopenia. Median survival of the group was 134 weeks, which was not significantly different from other approaches. CONCLUSIONS: Hemibody RT can be combined with chemotherapy as induction therapy and can be safely administered in a community setting. However, as administered here no survival advantage was demonstrated.

Adult↗
PubMed1997

Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice?

PURPOSE: Induction chemotherapy for advanced head and neck (H&N) cancer has been studied in clinical trials for more than two decades without clear demonstration of benefit for locoregional tumor control or overall patient survival. Nonetheless, its use has become a common community standard of practice in the United States (US). This report examines some of the factors that may have contributed to this phenomenon. MATERIALS AND METHODS: A mail survey was conducted of 300 US community cancer specialists (equally divided among otolaryngologists, radiation oncologists, and medical oncologists) to solicit their most frequent therapy approach for patients with locoregionally advanced, nonmetastatic H&N cancer. The rationale for selection of treatment strategy was identified by each respondent. RESULTS: Two hundred eighteen physicians (73%) completed and returned the survey, representing 47 US states. The single most common treatment approach reported for patients with locoregionally advanced H&N cancer was that of sequential chemoradiation (61%), specifically, induction chemotherapy with fluorouracil (5-FU)/cisplatin followed by radiation therapy. Four percent of respondents indicated that induction chemotherapy was administered within the context of a controlled clinical trial, whereas 96% indicated that therapy was administered off study. The primary objectives cited by respondents for the use of induction chemotherapy included the desire to improve locoregional tumor control (67%), to improve overall survival (56%), to maintain a spirit of multidisciplinary care (34%), to improve quality of life (29%), and to decrease distant metastases (26%). CONCLUSION: Review of the published trials between 1970 and 1995 and of the published meta-analyses show no clear evidence for an improvement in locoregional tumor control or survival for H&N cancer patients treated with 5-FU/cisplatin induction chemotherapy regimens. Nonetheless, this induction chemotherapy approach for advanced H&N cancer patients has become a dominant community practice in the US. Factors that may have contributed to this paradox are reviewed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group.

PURPOSE: The aim of this study was to examine whether, after preceding induction chemotherapy, simultaneous chemoradiotherapy is superior to radiotherapy alone. PATIENTS AND METHODS: Patients with non-small-cell lung cancer in inoperable stage IIIA or IIIB received induction chemotherapy with two cycles of paclitaxel 200 mg/m2 and carboplatin area under the curve 6 every 3 weeks. Patients without progression at restaging after induction chemotherapy were randomly assigned to radiotherapy (60 Gy) or chemoradiotherapy (paclitaxel 60 mg/m2 weekly). The primary end point was overall survival; secondary end points were time to progression, response, and toxicity. RESULTS: Three hundred three patients entered the study, and 276 completed induction chemotherapy. Two hundred fourteen patients were randomly assigned (radiotherapy alone: n = 113; simultaneous chemoradiotherapy: n = 101). Median follow-up time of all randomly assigned patients was 13.6 months (interquartile range [IQR], 6.4 to 29.0 months), and median follow-up time of the subgroup of censored patients (n = 52) was 37.4 months (IQR, 5.9 to 57.0 months; maximum, 76.1 months). Toxicities during the induction phase were mild. During radiotherapy, overall toxicity rates were not significantly different between the two arms. Median survival times in the radiotherapy group and chemoradiotherapy group were 14.1 months (95% CI, 11.8 to 16.3 months) and 18.7 months (95% CI, 14.1 to 23.3 months; difference not statistically significant, P = .091). Median time to progression significantly favored simultaneous chemoradiotherapy (11.5 months; 95% CI, 8.3 to 14.7 months) versus radiotherapy alone (6.3 months; 95% CI, 5.0 to 7.6 months; P < .001, log-rank test). CONCLUSION: Induction chemotherapy followed by chemoradiotherapy with weekly paclitaxel is feasible. Response, time to progression, and survival favor chemoradiotherapy compared with radiotherapy alone.

Aged↗
PubMed2003

Effect of green tea extract on the induction of ornithine decarboxylase and the activation of extracellular signal-regulated kinase in bladder carcinoma ECV304 cells.

According to several studies, green tea and individual catechins can inhibit the induction of ornithine decarboxylase (ODC), the key enzyme in the biosynthesis of polyamines. It has been suggested that the inhibition of ODC induction may offer an explanation to the anticancer and chemopreventive activities of green tea. In the present study, however, treatment of bladder carcinoma ECV304 cells with green tea extract (GTE) was not able to reduce the induction of ODC by fetal calf serum. Actually, in the absence of serum, GTE provoked a dose-dependent and remarkable induction of ODC activity. The induction of ODC, which could be elicited also by (-)-epigallocatechin 3-gallate, a major green tea component, required an early activation of extracellular signal-regulated kinase 1 and 2 (ERK), and both events appeared to be dependent on an alteration of the status of cellular thiol groups. Pretreatment with specific ERK or ODC inhibitors was able to prevent a late caspase activation but hardly affected the loss of cell viability provoked by GTE. In conclusion, to our knowledge, this is the first study showing that GTE can promote ODC induction in a tumor cell line.

Apoptosis↗
PubMed2004

Synergistic induction of the nicotinamide adenine dinucleotide-linked 15-hydroxyprostaglandin dehydrogenase by an androgen and interleukin-6 or forskolin in human prostate cancer cells.

The nicotinamide adenine dinucleotide-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and participates along with cyclooxygenases and lipoxygenases in controlling the cellular levels of prostaglandins and lipoxins. 15-PGDH could be induced by IL-6 and forskolin in addition to androgens in a time- and dose-dependent manner but not by other cytokines and growth factors in LNCaP cells. Concurrent addition of IL-6 and forskolin showed additive effect in the induction of 15-PGDH activity. However, combined addition of dihydrotestosterone (DHT) and IL-6 or DHT plus forskolin exhibited synergistic induction of 15-PGDH activity. The increase in enzyme activity was correlated with the expression of the enzyme protein as shown by Western blot analysis. The induction by DHT or IL-6 or forskolin or their combinations was inhibited by antiandrogen, casodex, in a dose-dependent manner, indicating that a functional androgen receptor was required for the action of any of these three agents. The induction by forskolin plus DHT or by either agent or by IL-6 alone was greatly inhibited by H-89, indicating the involvement of protein kinase A in the actions of forskolin, DHT, and IL-6. The induction of 15-PGDH by IL-6 was also blocked by some other protein kinase inhibitors, indicating the participation of MAPK, MAPK/ERK kinase, and STAT3 in the signaling pathway of IL-6. These results indicate that the induction of 15-PGDH by DHT, IL-6, and forskolin in LNCaP cells may involve a functional androgen receptor and phosphorylation-dependent multiple signaling pathways.

Androgen Antagonists↗
PubMed2003

EDL/MAE regulates EGF-mediated induction by antagonizing Ets transcription factor Pointed.

Inductive patterning mechanisms often use negative regulators to coordinate the effects and efficiency of induction. During Spitz EGF-mediated neuronal induction in the Drosophila compound eye and chordotonal organs, Spitz causes activation of Ras signaling in the induced cells, resulting in the activation of Ets transcription factor Pointed P2. We describe developmental roles of a novel negative regulator of Ras signaling, EDL/MAE, a protein with an Ets-specific Pointed domain but not an ETS DNA-binding domain. The loss of EDL/MAE function results in reduced number of photoreceptor neurons and chordotonal organs, suggesting a positive role in the induction by Spitz EGF. However, EDL/MAE functions as an antagonist of Pointed P2, by binding to its Pointed domain and abolishing its transcriptional activation function. Furthermore, edl/mae appears to be specifically expressed in cells with inducing ability. This suggests that inducing cells, which can respond to Spitz they themselves produce, must somehow prevent activation of Pointed P2. Indeed hyperactivation of Pointed P2 in inducing cells interferes with their inducing ability, resulting in the reduction in inducing ability. We propose that EDL/MAE blocks autocrine activation of Pointed P2 so that inducing cells remain induction-competent. Inhibition of inducing ability by Pointed probably represents a novel negative feedback system that can prevent uncontrolled spread of induction of similar cell fates.

Amino Acid Sequence↗
PubMed1995

Myogenesis in paraxial mesoderm: preferential induction by dorsal neural tube and by cells expressing Wnt-1.

Previous studies have demonstrated that the neural tube/notochord complex is required for skeletal muscle development within somites. In order to explore the localization of myogenic inducing signals within the neural tube, dorsal or ventral neural tube halves were cultured in contact with single somites or pieces of segmental plate mesoderm. Somites and segmental plates cultured with the dorsal half of the neural tube exhibited 70% and 85% myogenic response rates, as determined by immunostaining for myosin heavy chain. This response was slightly lower than the 100% response to whole neural tube/notochord, but was much greater than the 30% and 10% myogenic response to ventral neural tube with and without notochord. These results demonstrate that the dorsal neural tube emits a potent myogenic inducing signal which accounts for most of the inductive activity of whole neural tube/notochord. However, a role for ventral neural tube/notochord in somite myogenic induction was clearly evident from the larger number of myogenic cells induced when both dorsal neural tube and ventral neural tube/notochord were present. To address the role of a specific dorsal neural tube factor in somite myogenic induction, we tested the ability of Wnt-1-expressing fibroblasts to promote paraxial mesoderm myogenesis in vitro. We found that cells expressing Wnt-1 induced a small number of somite and segmental plate cells to undergo myogenesis. This finding is consistent with the localized dorsal neural tube inductive activity described above, but since the ventral neural tube/notochord also possesses myogenic inductive capacity yet does not express Wnt-1, additional inductive factors are likely involved.

Animals↗
PubMed1998

Neural crest induction in Xenopus: evidence for a two-signal model.

We have investigated the molecular interactions underlying neural crest formation in Xenopus. Using chordin overexpression to antagonize endogenous BMP signaling in whole embryos and explants, we demonstrate that such inhibition alone is insufficient to account for neural crest induction in vivo. We find, however, that chordin-induced neural plate tissue can be induced to adopt neural crest fates by members of the FGF and Wnt families, growth factors that have previously been shown to posteriorize induced neural tissue. Overexpression of a dominant negative XWnt-8 inhibits the expression of neural crest markers, demonstrating the necessity for a Wnt signal during neural crest induction in vivo. The requirement for Wnt signaling during neural crest induction is shown to be direct, whereas FGF-mediated neural crest induction may be mediated by Wnt signals. Overexpression of the zinc finger transcription factor Slug, one of the earliest markers of neural crest formation, is insufficient for neural crest induction. Slug-expressing ectoderm will generate neural crest in the presence of Wnt or FGF-like signals, however, bypassing the need for BMP inhibition in this process. A two-step model for neural crest induction is proposed.

Animals↗
PubMed2001

Fgf receptor signaling plays a role in lens induction.

We describe experiments showing that fibroblast growth factor receptor (Fgfr) signaling plays a role in lens induction. Three distinct experimental strategies were used: (1) using small-molecule inhibitors of Fgfr kinase activity, we showed that both the transcription level and protein expression of Pax6, a transcription factor critical for lens development, was diminished in the presumptive lens ectoderm; (2) transgenic mice (designated Tfr7) that expressed a dominant-negative Fgf receptor exclusively in the presumptive lens ectoderm showed defects in formation of the lens placode at E9.5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed that there is a genetic interaction between Fgfr and Bmp7 signaling at the induction phases of lens development. This manifested as exacerbated lens development defects and lower levels of Pax6 and Foxe3 expression in Tfr7/Tfr7, Bmp7(+/-) mice when compared with Tfr7/Tfr7 mice alone. As Bmp7 is an established lens induction signal, this provides further evidence that Fgfr activity is important for lens induction. This analysis establishes a role for Fgfr signaling in lens induction and defines a genetic pathway in which Fgfr and Bmp7 signaling converge on Pax6 expression in the lens placode with the Foxe3 and Sox2 genes lying downstream.

Animals↗
PubMed1987

Modulation of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase by adenosine, but not ketone bodies or ammonia in rat hepatocyte cultures. Possible significance for the zonal heterogeneity of liver parenchyma.

In primary cultures of rat hepatocytes the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was studied in the presence of putative local hormone and substrate modulators which form clear concentration gradients during liver passage such as adenosine, ketone bodies and ammonia. 1) Adenosine inhibited the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 50 and 200 microM up to 4 h after glucagon application; AMP had similar, adenine, inosine and guanosine had no effect. Adenosine was almost totally metabolized by the liver cells during the first 4 h of the induction period. The inhibitory action of adenosine was also observed using dibutyryl-cAMP or 8-bromo-cAMP as inducer; it could not be prevented by the adenosine receptor antagonist caffeine nor could it be mimicked by the selective adenosine receptor agonist N6-(phenylisopropyl)adenosine. 2) Acetoacetate suppressed the induction of phosphoenolpyruvate carboxykinase in a concentration-dependent manner between 5 and 20mM during the first 4 h after glucagon addition. beta-Hydroxybutyrate showed no effect. Neither starting with acetoacetate nor with beta-hydroxybutyrate did the cell cultures establish the thermodynamic equilibrium between the two compounds. 3) Ammonia did not affect induction of phosphoenolpyruvate carboxykinase at concentrations up to 2mM. Ammonia was converted to urea within the first 4 h; yet it remained at clearly hyperphysiological concentrations in the medium during that period. It is concluded that the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was modulated by the local hormone adenosine via a mechanism not involving adenylate cyclase and by acetoacetate via an unknown mechanism. The inhibitory action of adenosine may, that of acetoacetate can hardly be physiologically relevant.

Acetoacetates↗
PubMed2001

Induction of telomerase activity by irradiation in human lymphoblasts.

Neuhof, D., Ruess, A., Wenz, F. and Weber, K. J. Induction of Telomerase Activity by Irradiation in Human Lymphoblasts. Radiat. Res. 155, 693-697 (2001). Telomerase activity is a radiation-inducible function, which suggests a role of this enzyme in DNA damage processing. Since the tumor suppressor TP53 plays a central role in the regulation of the cellular response to DNA damage, our study explored the ability of ionizing radiation to change telomerase activity and telomere length in two closely related human lymphoblast cell lines with different TP53 status. TK6 cells (wild-type TP53) and WTK1 cells (mutated TP53) were exposed to different doses of X rays, and telomerase activity was measured by PCR ELISA at different times after irradiation. A dose-dependent increase in telomerase activity was observed. One hour after irradiation with 4 Gy, TK6 and WTK1 cells showed an approximately 2.5-fold increase; for lower doses (0.1 to 1 Gy), telomerase induction was seen only in TK6 cells. Telomerase induction was observed by 0.5 h after irradiation, with a further increase up to 24 h. Irradiated TK6 and WTK1 cells had longer telomeres (+1.3 kb) than unirradiated cells 14 days after exposure. Our data demonstrate a dose-dependent induction of telomerase activity and lengthening of telomeres by ionizing radiation in human lymphoblasts. Induction of telomerase activity by radiation does not generally appear to be controlled by the TP53-dependent DNA damage response pathway. However, for low doses, induction of telomerase requires wild-type TP53.

Cell Line↗
PubMed1996

Effect of nicardipine, a calcium antagonist, on induction of peroxisomal enzymes by dehydroepiandrosterone sulfate in cultured rat hepatocytes.

We examined the effect of nicardipine, a calcium antagonist, on the induction of peroxisomal enzymes, such as acyl-CoA oxidase and carnitine acetyltransferase, by dehydroepiandrosterone sulfate (DHEAS) and clofibric acid (CPIB), in primary cultured rat hepatocytes. Peroxisomal beta-oxidation and carnitine acetyltransferase activities were increased 11- and 20-fold, respectively, after 5 days of treatment with DHEAS (40 microM). However, 60 microM nicardipine significantly suppressed the induction of both of these activities by DHEAS to about 2-fold that of the control. This suppression was found to be both dose- and time-dependent. Immunoblot and Northern blot analyses of acyl-CoA oxidase revealed that suppression by nicardipine of the induction of peroxisomal beta-oxidation activity would be responsible for an increase in the amount of mRNA. In addition, the manner in which nicardipine suppressed the induction of peroxisomal beta-oxidation and carnitine acetyltransferase activity, was similar to that of clofibric acid. These findings suggest that in the calcium-dependent pathway, the mechanism for the induction of peroxisomal enzymes by DHEAS is basically the same as that by clofibric acid, a typical peroxisome proliferator. The present results also support our previous hypothesis that calcium may play an important role in the induction of these enzymes by peroxisome proliferators.

Animals↗
PubMedDate not supplied

A re-evaluation of intersubject variation in enzyme induction in man.

It has previously been suggested that subjects who are initially slow metabolisers of drugs have a greater potential for induction of their drug metabolising enzymes than subjects with initial high rates of metabolism. This inference is based on observations made of changes in half-life of antipyrine. The purpose of this presentation is to reanalyse data previously presented in the literature with reference to clearance, a more precise estimate of drug metabolising activity, and half-life a parameter derived from both clearance and distribution. In one study in non-obese subjects, approximately 80% of intersubject variation in the change of total antipyrine clearance can be explained by differences in body size, particularly differences in liver volume. Furthermore, the relationship between initial antipyrine half-life and the percentage change in antipyrine half-life following induction can be explained by the association between each parameter and body weight. These observations imply that the potential for enzyme induction, and therefore for drug interactions based on enzyme induction, is present in all subjects and that intersubject variance in steady-state drug concentrations are as wide following induction as before induction.

Antipyrine↗
PubMed2005

Urofollitropin and ovulation induction.

Anovulation is a common cause of female infertility. Treatment for women with anovulation is aimed at induction of ovulation. Ovulation induction with follicle-stimulating hormone (FSH) is indicated in women with WHO type II anovulation in whom treatment with clomifene citrate (clomifene) has failed. The majority of these women have polycystic ovary syndrome. The major disadvantages of ovulation induction with FSH are the risk of ovarian hyperstimulation syndrome and the risk of higher order multiple pregnancies. To reduce the rate of complications due to multiple follicular development, FSH should be administered using a chronic low-dose protocol with small dose increments. In women with WHO type I anovulation, an exogenous supply of luteinizing hormone (LH) is required to achieve an adequate follicular response to FSH treatment. Thus, ovulation induction with FSH is not the treatment of choice in these women. FSH is a hormone that stimulates follicle growth and oocyte maturation. Endogenous FSH is produced by the pituitary gland and exists as a family of isohormones exhibiting distinct oligosaccharide structures. FSH for exogenous administration is derived from urine or is produced as recombinant FSH. The commercially available FSH products all contain different mixtures of FSH isoforms. To determine the effectiveness of urofollitropin (urinary-derived FSH), a comparison with the other available gonadotropins was made (i.e. recombinant FSH and human menopausal gonadotropin). Urofollitropin and recombinant FSH appear to be equally effective and well tolerated for ovulation induction. Human menopausal gonadotropin is comparably effective to urofollitropin in terms of pregnancy outcomes. It remains unclear whether human menopausal gonadotropins have a higher risk of overstimulation and ovarian hyperstimulation syndrome compared to urofollitropin in women with polycystic ovary syndrome. In practice, recombinant products are more convenient to use but are also more expensive. Therefore, if availability is not an issue but costs are, there is still a place for the use of urofollitropins for ovulation induction.

Anovulation↗
PubMed2004

Induction of cytochromes P450.

The induction of cytochromes P450 (CYPs) has been appreciated for some time but an understanding of the mechanisms involved has been poorly understood until recently. The discovery of the role of nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) has provided a major trigger for research in this area. This work has provided an explanation for species differences in hepatic induction. The production of a PXR crystal structure in the presence and absence of known high affinity ligands has offered the possibility of predicting structures which may bind to the receptor and hence act as inducing agents in man. An improvement in the technology of hepatocyte culture, access to good quality human hepatocytes and the miniaturisation of cultured preparations has meant that the potential of this technique to predict induction in man has been realised. Molecular biological techniques have also proved essential in both the science and the quantitation of CYP induction. The use of transient transfection cell based systems coupled with reporter gene assays have meant that dose response curves can be generated for many chemicals. Assays have been developed to measure the increase of the corresponding CYP mRNAs in primary hepatocytes and some cell lines with a high degree of sensitivity and specificity (allowing the quantitation of closely related CYPs). Although CYP induction is not usually considered as a major drawback in drug development, the aim should be to eliminate or reduce the inducing effects of a new drug to a minimum. Thus, it is essential to increase our understanding of the complex mechanisms that regulate induction and to pay attention to both the dose and the physicochemical and structural properties of CYP inducing agents.

Animals↗