Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo.

BACKGROUND AND PURPOSE: Bendamustine with or without rituximab provides an effective and more tolerable alternative to the polytherapy cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) in the treatment of haematological tumours and is currently approved for the treatment of many haematological malignancies. Navitoclax (ABT-263) is a potent inhibitor of Bcl-2, Bcl-x(L) and Bcl-w, which has demonstrated efficacy in haematological tumours alone and in combination with other agents. This paper describes the in vivo efficacy of combining either bendamustine or bendamustine plus rituximab (BR) with navitoclax in xenograft models of non-Hodgkin's lymphoma EXPERIMENTAL APPROACH: Activity was tested in xenograft models of diffuse large B-cell lymphoma (DoHH-2, SuDHL-4), mantle cell lymphoma (Granta 519) and Burkitt's lymphoma (RAMOS). Activity was also monitored in a systemic model of Granta 519. KEY RESULTS: Navitoclax potentiated bendamustine activity in all cell lines tested. Bendamustine activated p53 in Granta 519 tumours, concurrent with activation of caspase 3. Navitoclax also improved responses to bendamustine-rituximab (BR) in a subset of tumours. CONCLUSIONS AND IMPLICATIONS: Navitoclax in combination with bendamustine and BR is a viable combination strategy for use in the clinic and demonstrated superior efficacy compared with previously reported data for navitoclax plus CHOP and rituximab-CHOP.

Noninvasive molecular imaging of apoptosis in vivo using a modified firefly luciferase substrate, Z-DEVD-aminoluciferin.

Apoptosis is a highly regulated process of programmed cell death essential for normal physiology. Dysregulation of apoptosis contributes to the development and progression of various diseases, including cancer, neurodegenerative disorders, and chronic heart failure. Quantitative noninvasive imaging of apoptosis in preclinical models would allow for dynamic longitudinal screening of compounds and facilitates a more rapid determination of therapeutic efficacy. In this study, we report the in vivo characterization of Z-DEVD-aminoluciferin, a modified firefly luciferase substrate that in apoptotic cells is cleaved by caspase-3 to liberate aminoluciferin, which can be consumed by luciferase to generate a luminescent signal. In two oncology models, namely SKOV3-luc and MDA-MB-231-luc-LN, at 24, 48, and 72 h after treatment with docetaxel, animals were injected with Z-DEVD-aminoluciferin and bioluminescent images were acquired. Significantly more light was detected at 24 (P<0.05), 48 (P<0.01), and 72 h (P<0.01) in the docetaxel-treated group compared with the vehicle-treated group, with caspase-3 activation at these time points confirmed using immunohistochemistry. Importantly, whereas significant differences between groups were detected as early as 24 h after treatment by molecular imaging, caliper measurements were unable to detect a difference for 4-5 additional days. Taken together, these data show that in vivo imaging of apoptosis using Z-DEVD-aminoluciferin could provide a sensitive and rapid method for early detection of drug efficacy, which could potentially be used by numerous therapeutic programs.

Lesions and identification of crystalline precipitates of glycoprotein IIb-IIIa antagonists in the rat kidney.

Two glycoprotein IIb-IIIa antagonists (xemilofiban, SC-54684A, and orbofiban, SC-57099B), which are platelet aggregation inhibitors, caused crystalline precipitates in the kidney tubules of rats at high dosages. Dogs were not affected. Depending on the degree of the precipitation, which was dosage dependent, and the location, which differed somewhat between the two compounds, the lesions varied from acute obstruction with tubule cell necrosis, nephron dilation, and sudden death with no inflammation to severe chronic pyogranulomatous inflammation. In order to understand the relevance of the lesions, it was important to identify the precipitates. This was technically challenging because the crystals were water soluble (dissolving in routine fixing and staining techniques) and were present in insufficient quantity to physically isolate. Techniques were devised to evaluate the crystals in situ in unstained frozen sections prepared without directly embedding the tissues in supporting medium, which interfered with the analyses. The crystals were analyzed in situ by infrared and Raman spectroscopy and time-of-flight secondary ion mass spectroscopy (TOF-SIMS). Uroliths found in the renal pelvis of one animal were analyzed by liquid chromatography/mass spectrometry. The resulting spectra showed that the crystals were the de-esterified acids of the parent compounds. This knowledge allowed us to predict that the crystalline precipitates would not be a hazard to humans because of the large multiples of the human dosage at which they occurred and because of differences in renal physiology between rats, dogs, and humans.

Community-based internal medicine residency training--a report on our first two years.

Since August, 1993, internal Medicine Associates Foundation, Inc. of Tupelo and the Department of Medicine, University of Mississippi Medical Center, have been cooperating in a program of community-based Internal Medicine residency training, the first effort of its kind in the state. We are pleased to report the program an unqualified success, for the residents themselves, the participating private physicians, and the Department as a whole. As one of only a handful of ambulatory care private practice relationships in the country (approximately five percent of Internal Medicine departments have such at present), we feel that ours can serve as a model for other programs to emulate. We therefore present a report on our program's background, organizational structure, curriculum, and future plans.

Organ donation and recovery in Mississippi: update 1996.

Over the last 10 years, solid organ transplantation has become increasingly successful and, in 1996, is the recognized standard of care for many end-stage organ diseases. Unfortunately, as this therapy has become more desirable, the demand for transplants has far outpaced the available supply of transplantable organs. Advances in organ preservation, surgical recovery techniques, centralized placement services and communication systems, as well as increased public awareness of the need have helped to increase organ availability. In addition, many transplant programs are now willing to make use of organs from "marginal" or "expanded" donors, particularly in urgent settings for liver and heart transplant recipients. The primary source of organs for Mississippi patients awaiting transplants is Mississippi donors. The Mississippi Organ Recovery Agency, an independent, non-profit agency, is the federally designated recovery organization for the state of Mississippi. This agency and the wait-listed recipients of the University of Mississippi Medical Center's Transplant Programs are critically dependent on appropriate recognition and referral of potential donors by the health professionals of Mississippi. Historically, Mississippi has one of the lowest organ donation rates in the United States. This will only change if physicians make every effort to offer their patients the option of organ and tissue donation, and if the organ and tissue recovery programs are successful in ongoing educational projects for health professionals and the general public.

Cyclosporine inhibits the renal response to L-arginine in human kidney transplant recipients.

To evaluate the association of cyclosporine (CsA)-related nephrotoxicity with nitric oxide (NO) and endothelin, the effects of L-arginine (LA) and branched-chain amino acid (BCAA) infusions on renal hemodynamics in 5 normal volunteers and 12 renal transplant recipients were assessed. In normal humans, LA, but not BCAA, reduced mean arterial pressure and renal vascular resistance while increasing RPF and urinary nitrate (NO3-) excretion. Group 1 included six transplant recipients not on CsA; Group 2 subjects (N = 6) were receiving CsA. In both groups, mean arterial pressure declined during the infusion of LA (116 +/- 4 to 109 +/- 4 mm Hg; P < 0.001) but not BCAA (116 +/- 3 to 115 +/- 3; P = not significant). In Group 1, LA increased RPF 33 +/- 13% (329 +/- 48 to 436 +/- 77 mL/min per 1.73 m2; P = 0.01) and GFR 37 +/- 16% (95 +/- 7 to 130 +/- 18 mL/min per 1.73 m2; P = 0.01); renal vascular resistance declined 27 +/- 6%. In Group 2, LA did not affect renal hemodynamics. No changes occurred with BCAA in either group. LA increased urinary NO3-excretion by 27 +/- 17% in Group 1 (P < 0.05), but only by 16 +/- 13% in Group 2 (P = not significant). Urinary endothelin excretion was higher in Group 2 subjects (10.1 +/- 1.3 versus 5.3 +/- 0.8 pg/mL of GFR, P < 0.01). LA-induced renal vasodilation is associated with the increased urinary excretion of NO3-.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical documentation of end-stage renal disease due to hypertension.

Hypertensive end-stage renal disease (ESRD) purportedly accounts for 25% of new ESRD patients each year in the United States, but remains poorly understood. Clinical features include normal renal function at diagnosis of hypertension, family history of hypertension, left ventricular hypertrophy, and minimal proteinuria. We evaluated clinical and historic data documenting the diagnosis of hypertensive ESRD in 43 patients with ESRD attributed to hypertension who were referred to our center for renal transplantation. Hypertensive ESRD patients were more likely to be black patients with left ventricular hypertrophy compared with our overall population. Few of the hypertensive ESRD patients had undergone kidney biopsy, none of whom had classic features of benign nephrosclerosis. Less than 5% of patients had hypertension documented at any time with normal renal function. Based on our review, it is clearly possible that the number of patients reaching dialysis and transplantation with renal failure attributed to hypertensive ESRD may be overestimated.

Multiple neuromuscular abnormalities in a paranoid schizophrenic.

A broad range of skeletal muscle fiber abnormalities has been reported previously in muscle biopsy specimens from psychotic patients. In our experience, individual patients manifest only a few types of lesions; but we now have studied a paranoid schizophrenic patient whose skeletal muscle fibers show virtually the entire range of morphologic abnormalities. In addition to the morphologic abnormalities of skeletal muscle fibers, we also noted increased branching of subterminal motor nerves with enlarged endplates and chronic elevations of serum creatine phosphokinase activity. Despite this, the patient had minimal clinical evidence of neuromuscular dysfunction. The variety of types of neuromuscular dysfunctions found in this patient suggests their etiology may be related.

Mean serum creatine kinase activity in patients with functional psychoses.

Increased serum creatine kinase (CPK) activity has been reported to be present during acute exacerbations of psychosis in the majority of patients with the major "functional" psychoses. It has also been demonstrated that mean serum CPK activity, ie, average daily serum CPK activity, is under genetic control. In this report, we present evidence for an association between the presence of a transient elevation of serum CPK activity beyond the upper limit of normal during psychotic episodes and relatively high mean serum CPK levels during the rest of hospitalization. The magnitude of the transient serum CPK elevation was correlated with mean serum CPK activity in psychotic patients. The mean serum CPK level was also correlated with the terminal innervation ratio, an indication of alpha motor neuron dysfunction. The incidence of serum CPK elevations in first-degree relatives of psychotic patients was significantly greater in patients with high mean serum CPK activity than in those with low mean serum CPK activity. High mean serum CPK activity may be an indication of an increase in permeability of the muscle cell membrane, which in turn may be due to some defect in the neurotrophic regulation of muscle physiology or an independent expression of muscle abnormalities.