Nis I. Nissen

Effect of verapamil on daunorubicin accumulation in Ehrlich ascites tumor cells

SummaryPrevious studies have demonstrated that verapamil may overcome resistance to anthracyclines. In vitro and in vivo experiments were performed on wild-type and resistant Ehrlich ascites tumor cells.Verapamil in concentrations of 25–50 μM enhances the accumulation of daunorubicin (DNR) in resistant cells to the same level as in wild-type cells. No significant effect of verapamil on influx or nuclear binding could be demonstrated, indicating that verapamil enhances DNR uptake by blocking active drug extrusion. Exposure of cells to a high concentration of Ca2+ did not influence the effect of verapamil on DNR accumulation, suggesting a different mode of verapamil action apart from the Ca2+-blocking effect. Attempts to circumvent acquired resistance to DNR in vivo with verapamil showed that the combination of the two drugs was more toxic than DNR given alone. The LD10 of DNR was determined as 3 mg/kg and the LD10 of the combination, as 2.5 mg/kg. The therapeutic effect of verapamil at a dose of 50 mg/kg and DNR of 2.5 mg/kg increased the life span of the mice by 50%. No difference was seen in the wild-type tumor in vivo.These data lead us to conclude that verapamil can reverse DNR resistance completely, but that verapamil at non-toxic dosage only reduces DNR resistance by 50% in vivo.

Clinical experience with bacteraemia in patients with leukaemia and allied neoplastic diseases.

134 bacteraemic episodes in 112 patients with leukaemia and allied disorders over a 5-year period were reviewed. The patients were divided, with respect to neoplastic disease, into 3 prognostic groups according to estimated periods of survival of years (group 1), months (group II) or weeks (group III). High mortality was correlated to group III, gram-negative rod bacteraemia and septic shock. Low leucocyte levels and intensive antineoplastic treatment did not adversely influence the prognosis of the bacteraemic patients. Appropriate antibiotic therapy was correlated with a significantly lower mortality, and it is concluded that aggressive antibiotic therapy is indicated when bacteraemia is suspected from clinical judgement.

Comparison of the Working Formulation of non-Hodgkin’s lymphoma with the Rappaport, the Kiel, and the Lukes-Collins Classifications. Correlations and prognostic value

The Rappaport classification of non-Hodgkin’s lymphoma [1] gained universal acceptance as a valuable basic diagnostic language for communication of therapeutic results among medical centers in the period 1968–75. Recognition that non-Hodgkin’s lymphomas represent neoplasms of the lymphocytic immune system has resulted in new classifications based upon modern concepts of the T- and B-lymphocyte systems [2, 3]. Other newer classification schemes have challenged the terminology used by Rappaport [4–6], and the Rappaport system itself has been modified several times [7–9]. The existence and the use of many histologic classifications for the non-Hodgkin’s lymphomas prompted the United States National Cancer Institute to sponsor a large international multi-institutional clinicopathologic study comparing six classifications. The results were published in 1982, and two important conclusions were reached [10]: ‘First, each system is successful in separating a large group of patients into subgroups with a spectrum of prognoses varying from good to poor survival. Second, no system appears superior to any other in this respect’. Based on this study, the investigators reached consensus on a ‘Working Formulation of non-Hodgkin’s Lymphoma for Clinical Usage’.

Increased uptake of actinomycin D in Ehrlich ascites tumour cells induced by daunorubicin

SummaryThe influence of anthracyclines on the uptake of actinomycin D in Ehrlich ascites tumour cells was studied in vitro. The anthracycline daunorubicin significantly increased the [3H]actinomycin D uptake both in whole tumour cells and in isolated nuclei of tumour cells. On the other hand, actinomycin D increased daunorubicin uptake only to a very small degree.Experiments with other intercalating drugs did not influence [3H]actinomycin D binding, suggesting a specific interaction between actinomycin D and the anthracyclines. The mechanisms behind this interference is discussed.The increased cellular uptake of actinomycin D in the presence of daunorubicin may have implications for antineoplastic combination chemotherapy.