Cancer research
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Comparative Study
Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo.
JM216 is a novel antitumor platinum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neurotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma) and a human tumor model (PXN109T/C ovarian carcinoma xenograft) was studied in vivo. ⋯ Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 +/- 0.11 mg/l) to 200 mg/kg (PUF Cmax, 2.4 +/- 0.44 mg/l; P > 0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after its oral administration to mice. Optimal antitumor activity, tolerance, and pharmacokinetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration schedule.
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The therapeutic options for the treatment of androgen-independent prostatic cancers are rather limited; this is mainly because our understanding of the local mechanisms involved in the control of androgen-independent proliferation of the tumor is still very poor. The present experiments have been performed to verify whether luteinizing hormone-releasing hormone (LHRH) agonists may possess a direct effect on the growth of the human androgen-independent prostate cancer cells DU 145 and whether a LHRH growth regulatory system may be present in these cells. The data have shown that two potent LHRH agonists (Zoladex and Buserelin) exert a significant and dose-dependent antiproliferative action on DU 145 cells, after 4 days of treatment. ⋯ To verify this hypothesis, DU 145 cells have been cultured in serum-free conditions, and treated with a LHRH antagonist for 4 days. The treatment resulted in a significant increase of cell proliferation, suggesting an inhibitory role for the LHRH system in the local regulation of cell growth. In conclusion, these data demonstrate that: (a) LHRH agonists exert a specific antiproliferative action on the human androgen-independent DU 145 cells; (b) an autocrine/paracrine LHRH (or LHRH-like) loop, which seems to be inhibitory on cell proliferation, is expressed in DU 145 cells.
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Three homologous alicyclic mixed amine cis-(NH3)(R-NH2)Cl2Pt(II) complexes, in which R = C3H5, C6H11, and C8H15 (complexes abbreviated C3, C6, and C8, respectively), were evaluated with reference compounds cisplatin and tetraplatin for antitumor activities and biochemical pharmacology in wild-type (murine leukemia L1210/0 and human ovarian A2780) and corresponding variant cell lines resistant to cisplatin (L1210/DDP and 2780CP) and tetraplatin (L1210/DACH and 2780TP). Cytotoxicities, measured by either a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or a clonogenic assay, were maximal for the C6 complex, which was up to 12-, 40-, and 6-fold more potent than C3 against wild-type, cisplatin-resistant, and tetraplatin-resistant models, respectively, and up to 2-fold more potent than C8 against these cell lines. In general, cross-resistance to mixed amine analogues was partial in cisplatin- and tetraplatin-resistant cells and decreased (in L1210/DDP and 2780CP) or increased (in L1210/DACH and 2780TP) with increase in the alicyclic ring size. ⋯ For instance, complex C8, which accumulated to the greatest extent in any given cell line, produced adduct levels that were similar to or lower than those produced by C6. A partial explanation for this observation was the demonstrated reduced rate of binding of C8 to DNA. This study has highlighted the significance of alicyclic ring size in modulating the potency, cross-resistance profile, and biochemical pharmacology of mixed amine platinum(II) complexes in sensitive and cisplatin- or tetraplatin-resistant tumor cells.
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Previous investigations have revealed that the human TE-671 MR human rhabdomyosarcoma xenograft selected in vivo for melphalan resistance (M. C. Rosenberg, et al., Cancer Res., 49: 6917-6922, 1989) is cross-resistant to a wide variety of alkylating agents and to bleomycin, but is collaterally sensitive to etoposide. ⋯ Measurement of additional enzyme activities that might be involved in DNA repair revealed significant elevations in DNA polymerase alpha (46 +/- 8 (SD) units/mg protein in TE-671, 69 +/- 6 units/mg protein in TE-671 MR, P < 0.05) and DNA polymerase beta (0.43 +/- 0.01 units/mg protein in TE-671, 0.78 +/- 0.12 units/mg protein in TE-671 MR, P < 0.05) but not DNA polymerase delta or total DNA ligase. Examination of topoisomerases by activity assays and Western blotting revealed a 2-fold increase in topoisomerase II and a 2-fold decrease in topoisomerase I in the TE-671 MR xenograft compared to the parental xenograft, apparently explaining the collateral sensitivity to etoposide and cross-resistance to topotecan. These results suggest that TE-671 MR xenografts contain multiple changes in activities of DNA repair-related proteins and other nuclear proteins that could contribute to alkylating agent resistance.
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Apoptosis in the androgen-sensitive Dunning R3327 PAP prostatic adenocarcinoma was studied during the post castration period of 14 days and compared with the ventral prostate. The mRNA expression of testosterone repressed prostatic message-2 and tissue-type plasminogen activator in the Dunning tumor and in the ventral prostate was analyzed by Northern blot experiments and immunohistochemical procedures. The degree of endonuclease-degraded genomic DNA was examined by gel electrophoresis. ⋯ BrdUrd immunodetection showed that castration induced an initial increase in the number of BrdUrd-positive epithelial cells in the ventral prostate. In the tumors, castration resulted in a decrease in BrdUrd-positive epithelial cells. It was concluded that in the androgen-sensitive prostatic Dunning R3327 PAP adenocarcinoma, the biochemical cascade leading to apoptosis is not activated by androgen withdrawal, as in the ventral prostate.