Inhibitor Of Cell Replication Research Articles

Docetaxel in ovarian cancer

Docetaxel, a semisynthetic taxane, is a potent inhibitor of cell replication and, similar to paclitaxel, promotes in vitro assembly of stable microtubules and, therefore, prevents the depolymerisation process. Docetaxel has a higher affinity for the tubulin subunit and is associated with a 100-fold greater phosphorylation of BCL-2 inducing apoptosis. Docetaxel in combination with carboplatin demonstrates similar activity to paclitaxel/carboplatin in the upfront management of advanced ovarian cancer with less neurological, but greater haematological toxicity. This article reviews the rationale and indications for the use of docetaxel in ovarian cancer.

Docetaxel (Taxotere) in the Treatment of Non-Small Cell Lung Cancer

Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.

Basic fibroblast growth factor regulates IGF-I binding proteins in the clonal osteoblastic cell line MC3T3-E1

In previous studies, we reported that basic fibroblast growth factor (bFGF) regulates insulin-like growth factor messenger RNAs and protein levels in the osteoblastic MC3T3-E1 cells. In the present study, we examined the expression of insulin-like growth factor binding proteins (IGFBPs) in MC3T3-E1 cells and determined whether bFGF altered IGFBP mRNAs and protein levels. Since previous studies suggested that IGFBPs can inhibit DNA synthesis stimulated by IGF-I, we wondered whether the mitogenic effect of bFGF was altered by exogenous IGFBP-3. Confluent MC3T3-E1 cells were serum-deprived for 24 h and then treated with bFGF for 6-24 h. In control cultures, MC3T3-E1 cells expressed the mRNAs for IGF-I, IGF-II, and IGFBP-2, 4, 5, and 6 but not IGFBP-1 or 3. A 24 h treatment with bFGF at 10(-8) M decreased IGF-I mRNA by 97%, IGF-II mRNA by 73%, IGFBP-2 by 64%, IGFBP-4 by 73%, IGFBP-5 by 95%, and IGFBP-6 by 65%. The inhibitory effect of bFGF on IGF-I and IGFBP mRNA levels was not altered by aphidicolin, an inhibitor of cell replication. bFGF 10 nM decreased IGF-I levels determined by radioimmunoassay after acidification by 45% and 72% at 24 and 48 h, respectively. Western ligand blot for IGF binding proteins revealed that MC3T3-E1 cells expressed IGFBPs of 24, 30, and 34 kD. Treatment with bFGF 10(-8) M decreased the levels of the 24 and 30 kD band at 24 h but increased the 34 kD band.(ABSTRACT TRUNCATED AT 250 WORDS)

The interaction of heparin and basic fibroblast growth factor on collagen synthesis in 21-day fetal rat calvariae.

We examined the interactions of the glycosaminoglycan, heparin, and recombinant human basic fibroblast growth factor (bFGF) on collagen synthesis in 21-day fetal rat calvariae. In calvariae treated for 96 h, heparin (25 micrograms/ml) and bFGF (10(-9) M) inhibited collagenase-digestible protein (CDP) labeling by 52 and 60% of control, respectively, and the combination further inhibited CDP labeling. Inhibition of CDP labeling by heparin (25 micrograms/ml) or bFGF (10(-9), 10(-8) M) was similar in the presence or absence of aphidicolin (30 microM) an inhibitor of cell replication. Heparin selectively inhibited CDP labeling in the osteoblast rich central bone but bFGF alone or in combination with heparin inhibited CDP labeling both in the periosteum and central bone. Heparin and bFGF alone decreased steady state levels of alpha 1(I)procollagen messenger RNA (mRNA) at 24 h and the combination further decreased mRNA levels. A high concentration of insulin-like growth factor-1 (IGF-1, 3 x 10(-8) M) reversed the inhibitory effect of heparin on DNA synthesis and CDP labeling. In contrast, IGF-1 could not reverse the inhibitory effects of bFGF on CDP labeling but enhanced the stimulatory effects of bFGF on thymidine incorporation into DNA. We conclude that the inhibitory effects of heparin and bFGF on CDP are independent of effects on cell replication. We further conclude that both heparin and bFGF inhibit collagen synthesis at a pretranslational site since they decreased procollagen mRNA levels in osteoblasts. However, the inhibition of collagen synthesis by heparin and bFGF appears to involve divergent pathways since exogenous IGF-1 could overcome the effect of heparin but not bFGF on collagen synthesis.

Biphasic Effects of Prostaglandin E2on Bone Formation in Cultured Fetal Rat Calvariae: Interaction with Cortisol*

Previous studies have shown that prostaglandin E2 (PGE2) has both inhibitory and stimulatory effects on the incorporation of proline into collagenase-digestible protein (CDP) in cultured fetal rat calvaria. The present studies were undertaken to analyze further these biphasic effects of PGE2. PGE2 increased [3H]thymidine incorporation at 24 h, and this effect was enhanced in the presence of cortisol (10(-8) and 10(-7) M). An inhibitory effect on CDP labeling was observed at 96 h with PGE2 (10(-6) M) in the absence or presence of indomethacin (10(-6) M), but not in the presence of cortisol (10(-8) or 10(-7) M). When the central osteoblast-rich bone and periosteum were analyzed separately, the inhibitory effect of PGE2, with or without indomethacin, was confined to the central bone. Addition of aphidicolin (30 microM), an inhibitor of cell replication, did not prevent the inhibitory effect of PGE2 on CDP labeling. Analysis of labeled collagen by polyacrylamide gel electrophoresis showed a decrease in labeling of type I collagen in central bone. Moreover, mRNA for alpha 1(I)procollagen was decreased, as measured by dot blot hybridization and Northern blot analysis. Cortisol (10(-8)-10(-6) M) decreased the labeling of CDP as well as noncollagen protein (NCP) at 96 h. In the presence of cortisol, PGE2 (10(-8)-10(-5) M) consistently stimulated labeling of CDP and NCP, with a greater increase in CDP, resulting in an increase in the percentage of collagen synthesized. In the presence of low concentrations of cortisol (10(-8) or 3 x 10(-8) M), PGE2 (10(-7) M) increased CDP labeling by 260-480%, and the absolute value was 145-160% of that in control cultures without any hormone addition. The stimulatory effect was seen in both central bone and periosteum, although absolute values for CDP and percentage of collagen synthesized were higher in central bone. PGE2 (10(-7) M) had similar effects on CDP at 24 and 96 h in the presence of cortisol, and the stimulation at 10(-7) M was the same in the presence and absence of aphidicolin, suggesting that it was not dependent on cell replication. Cortisol decreased labeling of type I collagen, determined by polyacrylamide gel electrophoresis, and alpha 1(I)procollagen mRNA levels, determined by both Northern and dot blot analysis. PGE2 reversed these effects, increasing both radiolabeled collagen type I chains and alpha 1(I)procollagen mRNA levels. These results indicate that PGE2 can regulate bone collagen synthesis at a pretranslational site.(ABSTRACT TRUNCATED AT 400 WORDS)

Ocular Toxicity of Intravitreal Taxol

AbstractTaxol is a drug isolated from the plant Taxus brevifolia and has been used as an antitumor agent.1 It is a potent inhibitor of cell replication by acting to stabilize microtubules and thereby completely inhibit fibroblast migration. Taxol has been found to be useful in inhibiting the development of tractional retinal detachments in experimentally induced proliferative vitreoretinopathy in rabbits.2,3 In this study, we injected 0.1 ml of taxol dissolved in 30% DMSO in balanced salt solution (BSS, Alcon Laboratories, Fort Worth, TX) as a single intravitreal injection into rabbit eyes at concentrations of 10−2 M, 10−3 M, 10−4 M, 10−5 M, 10−6 M, and 10−7 M. Severe toxicity to the lens and retinal toxicity were noted at taxol concentrations of 10−2 M. We determined that 0.1 ml of 10−5 M taxol or lower concentrations can be safely injected as a single intravitreal dose in the rabbit eyes without causing damage to ocular tissues.