2-aroylindoles, a novel class of potent, orally active small molecule tubulin inhibitors.

2-Aroylindoles with 5-methoxy-1H-2-indolyl-phenylmethanone (D-64131) as the lead structure were discovered as a new class of synthetic, small molecule tubulin inhibitors. By competitively binding with [(3)H]colchicine to alphabeta-tubulin and inhibiting microtubule formation, cycling cells were arrested in the G(2)-M phase of the cell division cycle. The proliferation of tumor cells from 12 of 14 different organs and tissues was inhibited with mean IC(50)s of 62 nM and 24 nM by D-64131 and D-68144, respectively, comparable with the potency of paclitaxel with mean IC(50) of 10 nM. By measuring the cytotoxicity in a human colon carcinoma cell model with ectopic ecdysone-inducible expression of the cyclin-dependent kinase inhibitor p21(WAF1), specificity toward cycling cells was demonstrated. In contrast to microtubule inhibitors from natural sources, 2-aroylindoles did not alter the polymerization-dependent GTPase activity of beta-tubulin and are not substrates of the multidrug resistance/multidrug resistance protein efflux pump. No cross-resistance toward cell lines with multidrug resistance/multidrug resistance protein independent resistance phenotypes became evident. In animal studies, no signs of systemic toxicity were observed after p.o. dosages of up to 400 mg/kg of D-64131. In xenograft experiments with the human amelanoic melanoma MEXF 989, D-64131 was highly active with treatment resulting in a growth delay of 23.4 days at 400 mg/kg. Therefore, D-64131 and analogues have the potential to be developed for cancer therapy, replacing or supplementing standard therapy regimens with tubulin-targeting drugs from natural sources.

Inhibin A/B in HMG or recombinant FSH ovarian stimulation with cetrorelix medication.

The inhibins are valuable factors in the assessment of the quality of an ovarian stimulation cycle. In spite of good clinical results with recombinant FSH and multiple dose LHRH- antagonist (Cetrotide((R))) administration, there remains a theoretical concern that in cycles stimulated with recombinant FSH, devoid of any LH activity, not enough endogenous LH is available to guarantee good follicle maturation. A total of 287 serum samples from 41 patients was assessed: 20 patients received ovarian stimulation with recombinant FSH, 21 patients with HMG and multiple dose Cetrotide administration. Inhibin A and B were measured on cycle days 2 and 6, the day of HCG administration, the day of embryo transfer as well as 7 and 14 days after the transfer. The two patient groups were similar with regard to age, amount of gonadotrophins required and number of follicles >18 mm and 15-18 mm. Inhibin A and B concentrations were comparable throughout the stimulation, thus indicating the equality of ovarian stimulation with recombinant FSH/HMG and midcyclic antagonist administration. Higher inhibin B concentrations throughout the stimulation were correlated with a higher oocyte yield. The small number of pregnancies prevented assessment of the relationship between inhibin B values and pregnancy rate.

Inhibin B on the day of HCG-administration is a predictive factor for failure in assisted reproduction cycles.

MATERIALS AND METHODS: This retrospective study was carried out in order to assess the value of inhibin B as a predictive factor for the assisted reproduction-outcome. Inhibin B on the day of HCG-administration (ovulation induction) was measured in 15 pregnant and 16 non-pregnant patients (defined as positive serum-HCG) and compared by single and multiple logistic regression analysis with classical predictive factors such as estrogen and oocyte number. Both groups were similar with respect to age and cause of infertility. RESULTS: While estrogen, FSH and LH at the HCG-day did not differ, inhibin B, the number of cumulus oocyte complexes and metaphase II -oocytes were statistically significantly different. In a single variable logistic model inhibin B, cumulus oocyte complexes and metaphase II oocytes showed significant correlation with pregnancy. When reassessed in a multiple variable logistic model only inhibin B maintained a considerable influence. Further inspection revealed, that the predictive inhibin B value at HCG-day <1200 pg/ml for failure of ART (assisted reproduction techniques) was 91%. Inhibin >1200 pg/ml showed 70% predictivity for pregnancy. CONCLUSION: In comparison to classical parameters inhibin B at HCG-day seems to be the better prognostic factor for the outcome of ART. Inhibin B <1200 pg/ml seems to be highly predictive for failure of ART.