Clinical relevance of P-glycoprotein expression in haematological malignancies

Although, generally speaking, haematological malignancies are chemotherapy-responsive tumours and high remission induction rates are obtained, disease-related death is the rule rather than the exception. The appearance of cell populations, resistant to multidrug-based chemotherapy, constitutes the major problem to achieve cures in these patients. Advances in cell biology have partly contributed to the elucidation of different multidrug resistance (MDR) mechanisms, which enable cells to survive the cytotoxic effects of multiple chemotherapeutic agents. Of these resistance mechanisms, the one that is referred to as classical MDR is the most extensively studied, both in the laboratory as well as in patients, and here we will focus on its clinical relevance in haematological malignancies. The classical MDR phenotype is caused by enhanced cellular drug efflux due to increased activity of a membrane-bound glycoprotein (P-glycoprotein) drug pump, that can pump out anthracyclines, anthracenediones, vinca alkaloids and epipodophyllotoxins, thereby actively lowering the intracellular drug concentrations to sublethal levels. As soon as molecular probes for the detection of MDR cells became available, clinical studies were initiated to answer three main questions. Do human tumour cells express P-glycoprotein? If so, is the expression indicative of a bad prognosis, c.q. resistant disease? And last but not least, can we interfere with the P-glycoprotein drug pump in the patient? Clinical data indicate that classical MDR may be involved in the development of drug resistance, especially in some haematological malignancies, such as acute myelocytic leukaemia (AML), non-Hodgkin's lymphomas (NHL), and multiple myelomas (MM). In almost all types of haematological malignancies, either untreated or treated, elevated P-glycoprotein levels have been reported, ranging from low to high. However, the acquisition of clinical MDR associated with P-glycoprotein expression occurs only in those diseases (for example, AML and MM) that are heavily treated with MDR-related drugs, probably by selection of pre-existing P-glycoprotein-expressing malignant cells. Since P-glycoprotein is found to be expressed on the membrane of normal haemopoietic progenitor cells as well, it seems likely that P-glycoprotein-positive haematological tumours develop by malignant transformation of P-glycoprotein-expressing normal haemopoietic counterparts. Especially for AML, convincing data have been reported in the literature to show that P-glycoprotein expression at diagnosis is a bad prognostic factor that predicts refractoriness. Using in vitro model systems for classical MDR, a large number of agents have been identified that can circumvent P-glycoprotein-mediated drug resistance, the so-called resistance modifying agents (RMA). Subsequently, clinical phase I and II studies have been initiated which combine the use of MDR-related drugs in conjunction with RMAs. The overall conclusions from such studies in AML, NHL, and MM are that modulation of drug resistance by RMAs seems promising and that further evaluation in prospective, randomized phase III trials is warranted

Different distribution of adriamycin in normal and leukaemic rats.

Adriamycin (ADR) accumulates in well-perfused organs in the rat. This effect is especially evident for long periods in marrow and spleen of healthy animals. In rats bearing the Brown Norway Acute Myeloid Leukaemia (BNML) the in vivo distribution is significantly different. Maximum ADR levels in those organs which are morphologically infiltrated by leukaemic cells are significantly lower than in normal rats, while the persistence of measurable ADR concentrations does not change. On the contrary, ADR concentrations in organs not infiltrated by leukaemic cells are the same or slightly higher than in normal rats. Possible causes for these differences are either the differential properties of normal and leukaemic cells in their uptake and excretion of ADR, or anatomical and vascular changes. It is evident that, significantly different from normal. This observation may help in the prevention of toxicity by drug monitoring in serum

Osmotic pressure of the soil solution: determination and effects on some glasshouse crops.

In a factorial experiment, calcium sulphate, sodium chloride and potassium nitrate were added to a loamy sand soil in various quantities. The experiment was carried out in an unheated glasshouse. The salt status of the soil was determined with the aid of different method of aqueous extraction. The results were correlated with the osmotic pressure of the soil solution. A close correlation was obtained with the conductivity of the saturation extract. Crop yields were correlated with the conductivity of the saturation extract and with the osmotic pressure of the plant sap. The correlation with the conductivity of the saturation extract was generally highest. With tomatoes, a clear relationship was found between the conductivity and the incidence of blotch on the fruits. In lettuce, there was a clear relationship between conductivity and the occurrence of tipburn. The yield reduction of some crops was significantly greater after the application of sodium chloride than after potassium nitrate. Apparently, this was caused by specific ion effects. The desirable salt level, the salt distribution in the soil and the determination of the osmotic pressure of the soil solution for routine soil-testing purposes are discussed. The curvilinear relationship between the salt level of the soil and the incidence of tipburn may be explained by the calcium uptake of the crop. (Abstract retrieved from CAB Abstracts by CABI’s permission

Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms

BACKGROUND: Extrapyramidal syndromes (EPS) are clinically relevant side effects of metoclopramide which are often not anticipated. PATIENTS AND METHODS: Two patients who received metoclopramide developed an acute dystonic reaction. Symptoms disappeared after biperiden or trihexyphenidyl were given. Molecular analysis of the CYP2D6 gene was performed using a PCR-based method. RESULTS: Both patients were homozygous for inactive CYP2D6 alleles (CYP2D6*4/*4 and CYP2D6*4/*5), which are associated with slow drug metabolism. CONCLUSION: Metoclopramide-induced acute dystonic reactions may occur in patients carrying a CYP2D6 genetic polymorphism

OCEAN: a randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma

Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival

Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdr1 phenotype

Summary The new non-immunosuppressive cyclosporin derivative SDZ PSC 833 (PSC) is a potent agent used to overcome typical multidrug resistance (MDR) associated with overexpression of themdr1 gene encoding for a P-170 glycoprotein. In the present study, the efficacy of PSC as compared with cyclosporin was determined in Chinese hamster ovary cell lines exhibiting different levels of resistance to colchicine (0, 0.1, 0.2 and 10 μg/ml, respectively). Low concentrations of PSC (8.2nm) increased the cytotoxicity of colchicine in cell lines expressing low levels of drug resistance. The concentration resulting in 50% cell survival (LC50 value) found for colchicine alone or in combination with PSC in the CHO-A3 cell line that was resistant to 100 ng colchicine/ml decreased from >500 to 200 ng/ml at 8.2nm PSC and to 500 ng/ml for colchicine alone to 500 ng/ml for colchicine used in combination with 8.2nm PSC and to <100 ng/ml for colchicine combined with 82 or 820nm PSC. At a concentration of 82nm PSC, the maximal effect in MDR reversal was observed in the cell lines exhibiting moderate resistance. In the highly resistant cell line, PSC (820nm) also reversed colchicine resistance. In drug-accumulation experiments, we obtained a 4-fold increase in intracellular doxorubicin accumulation using 820nm PSC. A comparison of PSC with cyclosporin revealed that a cyclosporin concentration 20-fold that of PSC was required to obtain the same sensitising effect. On the basis of these data, it may be concluded that PSC is a most promising chemosensitiser

Malignant histiocytosis: A reassessment of cases formerly classified as histiocytic neoplasms and review of the literature

Malignant histiocytosis (MH) and true histiocytic lymphoma (THL) are hematopoietic malignancies of the mononuclear phagocytic system distinguished from each other by clinical presentation and presumed cell of origin. THL present as a localized mass derived from the fixed tissue histiocyte which may or may not disseminate. MH originates from the circulating monocyte or tissue macrophage and is characterized by a syndrome of systemic symptoms, pancytopenia, adenopathy, hepatosplenomegaly, and wasting. The distinction between MH and THL is at times arbitrary and overlap exists between these syndromes. The clinicopathologic studies that defined these entities were performed prior to the development of immunophenotyping and other molecular techniques currently used to ensure proper classification of hematopoietic malignancies. Nine patients from the University of Minnesota originally diagnosed with MH were retrospectively analyzed using a panel of antibodies reactive against T cell, B cell, and myelomonocytic antigens. Only one patient was reclassified as a possible histiocytic malignancy after reevaluation. Similar immunophenotyping studies have also shown cases previously diagnosed as MH or THL express lymphoid antigens, and would now be classified as Ki-1 positive anaplastic large cell lymphoma (ALCL) or some other hematopoietic neoplasm. These results indicate true histiocytic neoplasms are extremely rare, and previous concepts concerning clinical presentation and therapeutic outcome of the entities are inaccurate. In this paper we summarize the results of multiple retrospective analyses of cases previously diagnosed as MH or THL, including our experience at University of Minnesota, to illustrate the overall rarity of these entities. The current literature on malignant histiocytic disorders is reviewed, and the clinical presentation of patients determined to have histiocytic malignancies using contemporary analytical techniques is discussed