Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

PURPOSE: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. METHODS: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. RESULTS: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. CONCLUSIONS: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels.

OBJECTIVE: Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients. DESIGN: Of 514 acromegalic patients treated with pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes. RESULTS: Under treatment with pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, P=0.04) for IGF1. Diabetic patients normalised for IGF1 required higher pegvisomant doses (18.9 vs 15.5 mg pegvisomant/day, P<0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg pegvisomant/day, P=0.11). CONCLUSIONS: Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.

Molecular modelling studies of new potential human DNA polymerase α inhibitors.

The human polymerase α (pol α) is a promising target for the therapy of cancer e.g. of the skin. The authors recently built a homology model of the active site of human DNA pol α. This 3D model was now used for molecular modelling studies with eight novel analogues of 2-butylanilino-dATP, which is a highly selective nucleoside inhibitor of mammalian pol α. Our results suggest that a higher hydrophobicity of a carbohydrate side chain (pointing into a spacious hydrophobic cavity) may enhance the strength of the interaction with the target protein. Moreover, acyclic acyclovir-like derivatives outperformed those with a sugar-moiety, indicating that structural flexibility and higher conformational adaptability has a positive effect on the receptor affinity. Cytotoxicity tests confirmed our theoretical findings. Besides, one of our most promising compounds in the molecular modelling studies revealed high selectivity for the SCC-25 cell line derived from squamous cell carcinoma in man.

Antitumor effects of guanosine-analog phosphonates identified by molecular modelling.

Aiming to address new drug targets, molecular modelling is gaining increasing importance although the prediction capability of the in silico method is still under debate. For an improved treatment of actinic keratosis and squamous cell carcinoma, inhibitors of human DNA polymerase alpha (pol alpha) are developed by docking nucleoside phosphonate diphosphates into the active site of pol alpha. The most promising prodrugs OxBu and OxHex were then prepared by total synthesis and tested in the squamous cancer cell line SCC25. OxBu and OxHex proved cytotoxic and antiproliferative in the nanomolar concentration range and thus exceeded activity of aphidicolin, the relevant model compound, and 5-fluorouracil, the current standard for the therapy of actinic keratosis. Interestingly, the cytotoxicity in normal human keratinocytes with OxHex was clearly less pronounced and even not detectable with OxBu. Moreover, cytotoxicity of OxBu in particular with the colorectal carcinoma cell line HT29 even surmounted cytotoxicity in SCC25, and other tumor cell lines were influenced, too, by both agents. Taken together, OxBu and OxHex may offer a new approach to cancer therapy, given the agents are sufficiently well tolerated in vivo which is to be suspected beside their chemical structure.

Human polymerase alpha inhibitors for skin tumors. Part 2. Modeling, synthesis and influence on normal and transformed keratinocytes of new thymidine and purine derivatives.

Recently, the three-dimensional structure of the active site of human DNA polymerase alpha (pol alpha) was proposed based on the application of molecular modeling methods and molecular dynamic simulations. The modeled structure of the enzyme was used for docking selective inhibitors (nucleotide analogs and the non-nucleoside inhibitor aphidicolin) in its active site in order to design new drugs for actinic keratosis and squamous cell carcinoma (SCC). The resulting complexes explained the geometrical and physicochemical interactions of the inhibitors with the amino acid residues involved in binding to the catalytic site, and offered insight into the experimentally derived binding data. The proposed structures were synthesized and tested in vitro for their influence on human keratinocytes and relevant tumor cell lines. Effects were compared to aphidicolin which inhibits pol alpha in a non-competitive manner, as well as to diclofenac and 5-fluorouracil, both approved for therapy of actinic keratosis. Here we describe three new nucleoside analogs inhibiting keratinocyte proliferation by inhibiting DNA synthesis and inducing apoptosis and necrosis. Thus, the combination of modeling studies and in vitro tests should allow the derivation of new drug candidates for the therapy of skin tumors, given that the agents are not relevant substrates of nucleotide transporters expressed by skin cancer cells. Kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogs.