There is a need for information on the bioavailability in pediatric patients of drugs from manipulated dosage forms when applied in combination with food and/or co-medication under realistic daily ...practice circumstances. We describe the development, validation and application of a dynamic, computer-controlled in vitro system mimicking the conditions in the upper gastrointestinal tract of neonates, infants and toddlers: TIMpediatric. Paracetamol and diclofenac in age-related food matrices and with esomeprazole co-medication were tested. The experiments showed relevant results on the impact of drug manipulation and co-medication on the availability for absorption of active compounds. Without ethical constraints, alternative approaches for oral dosing and new pediatric formulations can be studied in TIMpediatric with a high predictive value.
Mitosenes of both the pyrrolo- and pyrido1,2-aindole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with ...nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.
Acetyldinaline CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and ...toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a "full dose" of 23.7 mg/kg once daily (first group), a twice daily "half dose" of 11.85 mg/kg with an interval of 8 h (second group), or a "half dose" of 11.85 mg/kg once daily (third group). The drug-free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval in between, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or > 8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro-intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies.
The in vitro antiproliferative effect of docetaxel (Taxotere), paclitaxel (Taxol) and cisplatin was assessed in a range of human tumour types, including 25 tumour cell lines and 35 primary cultures. ...Additionally, 12 human normal bone marrow samples were analyzed. Seven laboratories, all members of the EORTC Preclinical Therapeutic Models Group (PTMG), have performed these tests, using their own individual assay procedures. In all comparisons docetaxel and paclitaxel were much more potent than cisplatin with IC50 values of the taxoids being in the nanomolar range. Docetaxel generally was two- to four-fold more cytotoxic than paclitaxel. The sensitivity profile of the cell lines, which was based on the IC50 values, indicated a certain degree of cross-sensitivity between paclitaxel and docetaxel (linear regression analysis; r = 0.73, p < 0.001). On the other hand, the sensitivity profile of cisplatin was different from the ones seen for docetaxel and paclitaxel, indicating that no cross-sensitivity exists between cisplatin and both taxoids.
RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs ...tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatment in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SRI and SRII, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo. Maximum supra-additivity for cis-Pt was afforded by divided doses of the drug (5 X 2.4 mg/kg/day) given immediately before X ray (5 X 1000 rad/day) on 5 consecutive days, although 3 other schedules also produced significant supra-additivity. Maximum supra-additivity for cyclo was seen for a single dose of 100 mg/kg followed 1 day later by a course of 5 daily X ray doses (5 X 1000 rad/day), and at least one other schedule produced almost as great an effect.
A series of di-n-butyltin(IV) compounds of the type di-n-butyltin(IV)(X-A-B-Y) with the (X-A-B-Y) being related to salicylic acid was tested in vitro for cytotoxic activity against tumour cells of ...the human A 204, MCF-7, T24, WiDr and IgR-37 cell lines using the PIT method. In each cell line the di-n-butyltin(IV) compounds displayed similar activity. As compared to cisplatin, the compounds were 4- to 10-fold more effective against A 204, MCF-7 and T24 tumour cells and slightly more effective against WiDr cells. The effectiveness against IgR-37 cells was similar for cisplatin and di-n-butyltin (IV) compounds.
A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole ...nucleus involves a Jacobson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120gag-abl tyrosine kinase compared with the parental 3T3 line. Compounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.
The concept of bioreductive alkylation as a mechanism of action of quinone-containing anticancer agents was investigated, using electrochemical techniques. According to this concept, an ...electrochemical step (reduction of the quinone ring) is followed by one or more chemical steps, leading to formation of the actual alkylating species. The proper use of electrochemical analysis of potential bioreductive alkylating quinones in the design of new analogs is limited. Up to now, the only electrochemical parameter frequently used in structure-activity relationship studies, is the half-wave potential of the quinone reduction. However, reliable information can only be obtained from the found value of this parameter when the reduction mechanism has been elucidated. Furthermore, it only gives information about the first step of the model. More detailed electrochemical analysis of potential bioreductive alkylating quinones, in combination with a biological evaluation, is required to gain more insight in their mechanism of action and to yield quantitative information about substituent effects on both the electrochemical and the chemical step(s) of the model. Results of such studies of a series of aziridinylquinones indicate, that the biological activity in vitro is correlated with the ease of protonation of the aziridines after quinone reduction, which is in accordance with the concept of bioreductive activation. No correlation with the ease of protonation of the aziridines prior to quinone reduction or with the quinone reduction step itself can be found.
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