Response of sensitive and resistant IgM immunocytomas to cis-diamminedichloroplatinum(II) does not correlate with the platination level or with the formation or removal of DNA adducts

 An IgM immunocytoma cell line sensitive to cis-diamminedichloroplatinum(II) (CDDP) and a subline with acquired resistance were grown in LOU/M rats. In a previous study with such rats that had been treated with a high dose of CDDP (10 mg/kg) the tumors did not show differences in cellular platinum content or DNA-adduct levels, either immediately after treatment or 24 h later. Recently, this high dose was found to overcome resistance. Therefore, the study was repeated with a 10-fold lower dose (1 mg/kg, i.v.). At 1 and 24 h after treatment, tumor and kidney tissue were assayed for cellular platinum (atomic absorption spectroscopy, AAS) and DNA platination (immunochemical detection of the four CDDP-DNA adducts). The results were compared with previous data. All tissues showed a linear response to dose with regard to platinum uptake as well as adduct formation, with no quantitative difference being seen between the tumors. Also the relative occurrence of the four adducts was very similar. Between 1 and 24 h, in tumors a substantial decrease occurred in both platinum content and adduct level; the kidneys showed little reduction, if any. At the lower CDDP dose a somewhat larger loss of platinum and removal of DNA adducts was observed for the resistant tumor, but these differences could be explained by “dilution”, as this tumor continues to grow after low-dose treatment (about 20% within 24 h). Since the strong difference observed between the tumors in sensitivity to CDDP cannot be attributed to differences in CDDP uptake, efficiency of adduct formation, or repair capability, other mechanisms are held responsible. Received 10 August 1995 / Accepted: 14 August 1996     

Platinum concentrations and DNA adduct levels in tumors and organs of cisplatin-treated LOU/M rats inoculated with cisplatin-sensitive or -resistant immunoglobulin M immunocytoma

Female LOU/M rats, bearing either a cisplatin (cisDDP)-sensitive or -resistant IgM immunocytoma, were sacrificed at 1 or 24 h after cisDDP administration (i.v., 10 mg/kg of body weight). Platinum levels, determined with atomic absorption spectroscopy, were in the order kidney much greater than liver greater than tumor greater than spleen in the 1-h samples. In the 24-h samples, more platinum was found in spleens than in tumors; the levels in the kidneys were the same as those measured at 1 h, in the spleens they were higher, and in livers and tumors they were lower than at 1 h after the injection; the greatest decrease occurred in the resistant tumor. cisDDP-DNA adducts were detected after chromatography of digested DNA samples isolated from these tissues and from blood cells. The quantitation of the four cisDDP-DNA adducts (Pt-G, Pt-AG, Pt-GG, G-Pt-G, the same as found previously in cisDDP-reacted DNA) was performed with specific antibodies, in the competitive enzyme-linked immunosorbent assay. The cisDDP-DNA adduct levels in the various 1-h tissue samples showed the same ranking order as the platinum levels. The blood samples contained the lowest amount of adducts. Because of the high platinum level in the kidneys (26 mg/kg of wet tissue), the adducts in this organ also could be determined with atomic absorption spectroscopy (the four adducts comprised about 400 fmol/micrograms of DNA). Comparison of the atomic absorption spectroscopy and enzyme-linked immunosorbent assay data showed excellent agreement. Except for the kidney, all samples showed a decrease in adduct level between 1 and 24 h after cisDDP treatment. The data on the tumors indicated that the difference in susceptibility to cisDDP between the sensitive and resistant tumors is not due to a decreased platinum content or reduced DNA adduct formation in the resistant tumor.     

Intensity discrimination capacity of retinal ganglion cells of a tree shrew ( Tupaia chinensis)

Responses of single retinal on-centre ganglion cells were recorded in order to study the intensity discrimination threshold behaviour. A Poisson distribution fitted pulse number distributions of the spikes in the burst evoked by short duration stimuli presented within the receptive field centre of sustained units. A normal distribution was found for transient units. The dependence of the mean, standard deviation and regularity of the pulse number distribution on stimulus intensity mimicked the behaviour of the statistical parameters of the maintained activity as a function of background intensity. The transient cells displayed statistical characteristics which are found also in psychophysical studies. These cells, therefore, are assumed to be mainly involved in intensity discrimination.The dynamic range of ganglion cells in response to short duration stimuli is relatively narrow, 1 log unit, so the Weber law which is valid over many log units cannot be explained with the single-channel detection model. A multichannel energy summation model yields a threshold curve that closely resembles psychophysically measured curves.The psychophysical dependency of the discrimination threshold on background intensity level as investigated by Thijssen and Vendrik (1971) could be explained from the responses of both types of cells.     

Intensive cytoreductive therapy followed by autologous bone marrow transplantation for patients with hematologic malignancies or solid tumors

Fifty patients were studied. Twenty patients with non-Hodgkin's lymphomas (NHL) of high-grade malignancy and 21 patients with acute leukemia (AL) were treated with high-dose cyclophosphamide and total body irradiation, and three patients with Hodgkin's disease (HD) and six patients with solid tumors were treated with high-dose cyclophosphamide and VP16-213. Those procedures were followed by autologous bone marrow transplantation (ABMT). All patients had received conventional chemo(radio)therapy before the ABMT procedure. Although remissions were obtained in patients with cytotoxic drug-resistant diseases (lymphomas and solid tumors), none has become a long-term survivor, as occurred also in patients with solid tumors in partial remission (PR). Two of five patients with NHL in PR at the time of ABMT have become long-term disease-free survivors (28+, 56+ months). Ten patients with NHL were treated in complete remission (CR) and seven are in unmaintained CR; four with long follow-up (14+ to 59+ months). All patients with AL were treated in CR; two patients received ABMT in second CR, and both relapsed. Ten of nineteen patients in first CR relapsed; eight are alive in CR, five with long follow-up. Four deaths were therapy-related, all were patients in poor clinical condition. Intensive cytoreductive therapy followed by ABMT can produce prolonged disease-free survival (and probably cure) in a fair number of patients with poor risk NHL in CR and PR and probably also in patients with acute myeloblastic leukemia in first CR. This procedure was not successful in achieving long-term disease-free survival in patients with refractory lymphomas or solid tumors.