Expression of Friend leukemia virus and spleen focus-forming virus-specific sequences in erythroid bursts and granulocyte-macrophage colonies from spleen and marrow of mice infected with Friend leukemia virus.

A large number of studies have been carried out to identify the Friend leukemia virus (FV) target cell(s). In FV-infected mice, the kinetics of "primitive" erythroid burst-forming units (P-BFU-E) is perturbed, and their proliferative rate is enhanced. These results indirectly suggest, but do not prove, that cycling P-BFU-E may serve as FV target. In vitro infection studies showed that normal erythroid colony forming units (CFU-E) and "mature" erythroid burst-forming units (M-BFU-E) are targets for FV, while the largely out-of-cycle normal P-BFU-E are not. In an attempt to shed light on these aspects, we have evaluated the expression of viral cytoplasmic RNA sequences in pools of colonies generated by P-BFU-E and granulocyte-macrophage colony forming units (CFU-GM) from spleen and marrow of polycythemic Friend virus (FVP)-infected mice, as measured by liquid hybridization with FVP- or spleen focus-forming polycythemic virus (SFFVp)-specific DNA probes. Moreover, similar assays were performed on RNAs derived from whole spleen or bone marrow from mice treated with FVP or the anemic strain of Friend virus (FVA). Control studies were performed on corresponding colonies and whole tissues from normal animals. FVP- and SFFVp-specific sequences are more abundant in RNA extracted from infected spleen as compared to marrow by a 10-fold factor. On the other hand, FVP and SFFVp-specific sequences are expressed at a comparable level in both P-BFU-E- and CFU-GM-derived colonies from spleen or marrow of FVP-treated mice. Since in vitro spread of FVP infection was excluded by control studies with addition in culture of antibody to the viral glycoprotein with a molecular weight of 70,000 (gp70) these results indicate that P-BFU-E and CFU-GM are infected in vivo by FVP.

Treatment of acute myelogenous leukemia in children: results of the Italian Cooperative Study AIEOP/LAM 8204.

One hundred thirty-three children with acute myelogenous leukemia (AML) entered the multicenter Pediatric Branch of the Italian Association Against Leukemia trial AIEOP/LAM 8204 between July 1982 and May 1986. Induction therapy consisted of two courses of daunomycin (DNM) plus cytosine arabinoside (Ara-C). Those patients who achieved remission were given four courses of consolidation with DNM, 6-thioguanine (6-TG) and escalated doses of Ara-C followed by six courses of sequential continuation therapy using monthly pairs: etoposide (VP-16)/Ara-C, Ara-C/6-TG, and DNM/Ara-C. Periodic intrathecal Ara-C was used for CNS prophylaxis. One hundred seven (80%) children achieved complete remission (CR). Kaplan-Meier estimates of 3-year disease-free survival (DFS) and event-free survival (EFS) are 41% and 33%, respectively. Relapses occurred in 34 patients after 5 to 97 weeks (32 marrow; 2 marrow plus CNS). Overall, 14 patients died of complications during treatment (nine during induction; five during the postremission phase), mostly from infection. Risk factor analysis showed that induction failures occurred predominantly in children with French-American-British (FAB) M5 and in those with elevated leukocyte counts; by step-up Cox analysis, only FAB subtype was predictive of remission success. None of the variables examined was significant for predicting the duration of remission. Hyperleukocytosis was predictive of a significantly worse EFS rate. These results are encouraging and further support the use of intensive chemotherapy programs for childhood AML.

P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia.

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment. PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)-positive. dnr 100 mg/m(2) was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography. RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 micromol/L in Pgp-negative samples and 13.5 micromol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 micromol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P<.05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed. CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.

PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.

The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

Altered glucoregulatory response to physiological infusions of epinephrine and glucagon in hyperthyroidism.

To study the mechanism of altered glucose homeostasis in hyperthyroidism, the effects of a 2-h physiological infusion of epinephrine (0.05 microgram/kg x min) or glucagon (3 ng/kg x min) on glucose kinetics and glucoregulatory hormones were determined in nine normal subjects and five untreated hyperthyroid patients. Under basal conditions, hyperthyroid patients exhibited increased glucose turnover (2.2 +/- 0.09 vs. 1.62 +/- 0.1 mg/kg x min in normals), a modest hyperglycemia, hyperglucagonemia, and normal levels of plasma insulin, cortisol, and GH. In normal subjects, epinephrine induced a sustained increase in plasma glucose (45 mg/dl), reflecting a transient 100% rise in glucose output, and a sustained 28% decrease in glucose clearance. In hyperthyroid patients, the rise in plasma glucose was significantly lower (22 mg/dl) due to a smaller but sustained increase in glucose output (45%) and the lack of a fall in glucose clearance. Plasma insulin rose to a peak 80% higher than baseline in hyperthyroid patients, whereas in normals it initially declined and then rose to levels 50% higher than basal. Plasma glucagon displayed only minor changes in both groups. Glucagon infusion induced similar increments in plasma glucagon levels in the two groups (120-150 pg/ml). Insulin, cortisol, and GH remained unchanged. Plasma glucose rose by 4 mg/dl in hyperthyroid patients and by 11 mg/dl in normal subjects. The net increments were significantly lower in the former group (P < 0.05-0.01). Glucose output increased by 40% in normals and returned to baseline by 75 min, whereas it increased by only 15% in hyperthyroid patients and remained above baseline until the end of the infusion. Glucagon had no appreciable effect on glucose clearance in either group. We conclude that hyperthyroidism is characterized by 1) increased glucose turnover and hyperglucagonemia in the basal state, 2) a reduced glucemic response to physiological infusions of epinephrine and glucagon, 3) a sustained response of glucose production to epinephrine and glucagon, and 4) the lack of epinephrine-induced suppression of glucose clearance, presumably due to an exaggerated response of insulin secretion to epinephrine.

Recombinant leukocyte interferon alfa-2a in the treatment of mycosis fungoides.

This study was designed to evaluate the efficacy and tolerability of recombinant leukocyte interferon alfa-2a (Hoffmann-LaRoche) as single agent in patients with histologically confirmed Mycosis Fungoides. The protocol consisted of a 12 week induction with subcutaneous interferon, escalating from 3 up to 18 million units daily, and a 6 or 9 month maintenance phase for complete or partial responses, respectively, with 18 million units 3 times weekly. 12 patients are evaluable: 5 are in complete remissions, 6 are partial remissions, and one had disease progression. Alfa-2a interferon was well tolerated: only 3 patients had WHO grade IV organ toxicity. Our study documents that recombinant leukocyte alfa 2a is a highly active agent in untreated patients with Mycosis Fungoides. Finally, the dose schedule chosen in this study allows alfa-2a interferon administration on an outpatient basis.

Climacteric symptoms and control of the cycle in women aged 35 years or older taking an oral contraceptive with 0.150 mg desogestrel and 0.020 mg ethinylestradiol.

In a multicenter prospective trial, 58 healthy women aged between 35 and 49 years were studied for one year (639 cycles) while taking an oral contraceptive (OC) containing desogestrel 0.150 mg and ethinylestradiol (EE) 0.020 mg. Efficacy, control of the cycle, side effects, complaints, and climacteric symptoms were monitored after 3, 6, 9 and 12 cycles. No pregnancies occurred during the study period. Spotting gradually decreased from 29.3% in cycle 1 to 4.2% in cycle 12, while breakthrough bleeding (BTB) disappeared after cycle 7. One case of superficial thrombophlebitis and 3 cases of minor side effects were registered. With regard to the complaints, breast tenderness, headache, and depression gradually decreased during the study (basal vs. 12-month data: 50.9% vs. 31.2%, 48.3% vs. 18.7%, 39.6% vs. 20.8%, respectively), while nausea disappeared after three months. A significant treatment-dependent reduction of climacteric symptoms was obtained after cycle 3 and this tendency was maintained up to cycle 12. No changes were registered in body mass index (BMI) or blood pressure.

Desogestrel versus gestodene in oral contraceptives: influence on the clinical and histomorphological features of benign breast disease.

Forty-four female volunteers asking for oral contraception, affected by symptomatic benign breast disease (BBD) were evaluated to compare the effects on mastalgia and breast nodularity of two different low dose oral contraceptives (OCs), containing 20 micrograms [corrected] ethinylestradiol + 150 micrograms desogestrel (EE+D) and 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE+G), respectively. Physical examination, bilateral thermography, X-ray and/or ultrasonography of breast, and needle and screw-needle biopsies of mammary tissue were performed in all patients before OCs administration and after six cycles of treatment. OCs administration caused an overall improvement of mastalgia in 53%. Breast nodularity improved only in 8% of patients in both groups. Epithelial tissue modifications in mammary biopsies were observed, with involutive and/or secretory histomorphological and ultrastructural changes, frequently coexisting in different areas of the same breast.

PIP: In Italy, researchers compared data on 22 women who used the low-dose oral contraceptive (OC) containing 20 mcg ethinyl estradiol and 150 mcg desogestrel (EE+D) with data on 22 other women who used the low-dose OC containing 30 mcg ethinyl estradiol and 75 mcg gestodene (EE+G) to determine the pharmacological effects of the 2 OCs on women affected by mastalgia and breast nodularity. Clinicians performed physical exams, bilateral thermography, X-ray and/or ultrasonography of breast and needle and screw-needle biopsies of mammary tissue before OC administration and after 6 cycles of OC treatment. An overall improvement of mastalgia and breast nodularity occurred in 53% and 8% of all patients, respectively. There were no significant differences between groups. Among EE+D treated women, a marked secretory attitude in breast epithelial cells occurred, probably due to a prominent progestin effect. Both OCs increased the number of cytoplasmatic organules and intraluminal secretory material without any apparent increase of cell proliferation. The observed involutive and/or secretory histomorphological and ultrastructural changes often occurred in different areas of the same breast. These results suggest that low dose OC use by women affected by benign breast disease improves mastalgia but not breast nodularity.

Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC).

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr 1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24 h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

[SDZ PSC 833: a novel modulator of MDR]. / SDZ PSC 833: un nuovo modulatore della MDR.

SDZ PSC 833 is a novel compound able to reverse the resistance to chemotherapy of cancer cells with the multidrug resistance (MDR) phenotype by inhibiting the 170 kd P-glyco-protein (P-gp). In vitro studies show that SDZ PSC 833 directly interacts with, but is not transported by P-gp, although the exact mechanism of action has not yet been defined. In cells with the MDR phenotype, intracellular concentration of various P-gp-transported anticancer drugs is restored to the same level as in sensitive cells by SDZ PSC 833 concentrations of 0.8 microM to 3.0 microM. In vivo SDZ PSC 833 was highly active in potentiating the anti-tumour activity of all tested anticancer drugs (ACs) in both sensitive and MDR tumours. Sensitivity of non-MDR tumours was increased by SDZ PSC 833 through pharmacokinetic interactions, that result in enhanced area-under-the-curve (AUC) of P-gp-transported ACs. However, an increased AC bioavailability is not sufficient to explain the therapeutic benefit of SDZ PSC 833 co-treatment in MDR tumour-bearing mice: in these animals, no survival increase could be achieved with the AC alone by simply increasing the cytotoxin dosage up to doses that were severely toxic for the non-tumour-bearing mice. In a series of phase I/II studies, the recommended doses of SDZ PSC 833 were established at: 10 mg/kg/day i.v. as a 24-hour continuous infusion after a 2 mg/kg loading dose as a 2-hour infusion; 20 mg/kg orally divided four times daily in solid tumours or 16 mg/kg orally divided four times daily in multiple myeloma. The dose limiting toxicity of SDZ PSC 833 is ataxia, which appears to be reversible and dose-related. Moreover, a predictable change in pharmacokinetic parameters of concomitantly administered P-gp-transported AC(s) which usually necessitate a 30-60% reduction from the standard dose of the AC in order to maintain the same time-exposure and dose-related toxicity of the cytotoxic drug alone. The results of experiments both in vitro and in vivo suggested that adequate blood levels (i.e. > or = 1.0 microM) of SDZ PSC 833 must be reached before and maintained during the administration of concomitant AC(s), in order to maximally reverse MDR. At the recommended doses, blood concentrations exceeding 1000 ng/mL (1.0 microM) can be achieved after both i.v. and oral administration. Indeed, SDZ PSC 833 concentrations that fully reverse MDR in vitro are achievable in vivo, plasma samples from patients treated with SDZ PSC 833 restored the sensitivity of MDR human sarcoma cells to paclitaxel, etoposide and doxorubicin. Clinical studies completed so far aimed first to determine the dose of both SDZ PSC 833 and the concomitant AC(s) to be used in ongoing pivotal trials. These studies accrued advanced stage cancer patients, however, tumour responses have been observed in both solid and hematological tumours. The in vitro finding that treatment with SDZ PSC 833 may suppress the activation of the MDR1 gene and prevent the emergence of resistant cancer cell clones with the MDR phenotype might support the use of this MDR modulator in earlier stages of disease.

Modulation of multidrug resistance (MDR) in hematological malignancies.

The term multidrug resistance (MDR) describes the observation that tumour cell lines can become cross-resistant to several structurally unrelated chemotherapeutic agents after exposure to a single cytotoxic drug. In hematological malignancies, MDR is most often associated with overexpression of P-gp, a 170-kd transmembrane glycoprotein encoded by the human MDRI gene. Indeed, P-gp expression has been correlated with drug sensitivity and clinical outcome in several studies in acute myelogenous leukemia (AML), multiple myeloma (MM), and malignant lymphomas (NHL). A large number of compounds 'off the shelf' have been investigated for their ability to reverse the P-gp mediated MDR. However, most of these agents produced severe toxic effects at doses required to effectively block P-gp function, and modulation of P-gp in normal tissues can affect the pharmacokinetics and, thus, the toxicity of the associated chemotherapeutic agents. Phase I/IIa trials with third generation MDR modulators, such as valspodar, show that these new agents can be safely administered in combination with different chemotherapy regiments after dose adjustments of cytotoxic drugs that a P-gp substrates. Moreover, MDR reversal by valspodar has been demonstrated in the patients with AML, multiple myeloma, and non-Hodgkin's lymphoma. The definition of the clinical benefits of using MDR modulators in haematological malignancies and their full extent awaits the conclusion of the ongoing randomized phase III trials with valspondar in either newly diagnosed or resistant relapsed AML patients, and in multiple myeloma patients who have failed front-line treatment.

Reducing workers' dust exposure during bag stacking in enclosed vehicles.

The Bureau of Mines has evaluated cost effective systems to ventilate enclosed vehicles being loaded directly with bagged product material at mineral processing plants. This evaluation included both forms of transportation: railcars and trailer trucks. The goal of this research was to lower the dust exposure of workers stacking bags in these enclosed vehicles; these workers usually have the highest dust exposures in the entire processing plant. The problem occurs because there is no mechanical ventilation inside these vehicles. As the vehicle is being loaded, dust concentrations increase to substantial levels because released dust has no means of exiting the vehicle or of being diluted with fresh air. In cases where the dust is hazardous, as with silica sand, this may present a serious health hazard. This research project was a two-step effort. The first step was a qualitative laboratory evaluation performed in a railcar to compare different types of ventilation systems (blowing, exhaust, and push-pull systems) using a methane (CH4) tracer gas technique. An exhaust system located over the snake conveyor was the most effective system at reducing gas levels in and around the bag stacker's work area. The second step then involved a field evaluation at a silica sand processing plant to determine the system's effectiveness in the actual work environment. Three different versions were evaluated in an attempt to optimize the exhaust ventilation system's effectiveness. The most effective version involved exhausting 54.5 m3/min (2000 ft3/min) through a fiberglass tube located 1.1 m past the end of the slinger at a 2.0-m height so as not to interfere with the bag stacker's job function.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmaceutical industry and oncology in central and eastern Europe.

Major opportunities exist for patients, investigators and the pharmaceutical industry in oncology drug development in Central and Eastern Europe. Novel therapeutics may be offered for investigational use in selected centres capable of adherence to Good Clinical Practice (GCP). Requirements for participation in oncology clinical trials include the availability of experienced qualified investigators highly motivated to conform with the principles of GCP (International Harmonization (ICH) guidelines); availability of appropriate Institutional Review Board for Human Subjects (IRB), access to appropriate patient populations, access to individual patient data, acceptance of possible audit by sponsoring companies and the Food and Drug Administration (FDA), and a willingness to participate in the generation of new knowledge. Patients gain through access to novel therapeutics. We have had success in performing clinical trials to international standards in Central and Eastern Europe. This experience will be described.

Effects of an oral contraceptive combination containing 0.150 mg desogestrel plus 0.020 mg ethinyl estradiol on healthy premenopausal women.

Twenty-six healthy premenopausal outpatients from the Menopause Clinic of the University of Bologna were treated with a combination pill containing 0.020 mg of ethinyl estradiol and 0.150 mg of desogestrel for one year. Throughout the treatment period, clinical and laboratory monitoring was periodically performed, and women were asked about the occurrence of climacteric symptoms. This formulation relieved climacteric symptoms, and did not adversely affect lipids and clotting factors, except for a slight increase in serum triglycerides. Laboratory data also suggest a beneficial effect on bone metabolism.

In vitro pharmacological purging of human bone marrow is enhanced by the use of lonidamine.

Lonidamine (LND), previously reported as a useful antitumor substance in combination with physical or chemical agents, has been studied for its capacity in increasing pharmacological elimination in vitro of residual tumor cells from human bone marrow. Different drugs were tested in association with LND against mixtures of human bone marrow and a tumor cell line, clonogenic human leukemic blast progenitors, and normal human bone marrow precursors. The results demonstrated that LND increased the efficacy of anthracycline derivatives (Adriamycin, Mitoxantrone) both on the tumor cell line and on the leukemic blast progenitors, while VP-16 or ASTA-Z 7654 was not affected by the same substance. The toxicity on normal stem cells reflected that of each drug and was not modified by the addition of LND. While a consistent dose-dependent CFU-GM reduction was observed immediately after treatment with the different drugs, a complete recovery was reached after 7 and 14 days of long-term marrow cultures. Because of the low toxicity and the efficacy demonstrated in association with certain agents in increasing tumor cell elimination in vitro, LND could play an important role in in vitro purging prior to autologous bone marrow transplantation.

Globin chain synthesis in single erythroid bursts from cord blood: studies on gamma leads to beta and G gamma leads to A gamma switches.

Erythroid bursts from cord or adult blood were grown in methylcellulose cultures (3 international units of erythropoietin per plate). On day 13, single bursts were picked up and reincubated for 16-24 hr with [3H]leucine. Radioactive globin chains [alpha,beta,G gamma, and A gamma (Ala-136)] were analyzed by either isoelectric focusing on polyacrylamide gels and fluorography or carboxymethylcellulose chromatography. In all cases, alpha to non-alpha globin radioactivity ratios were close to 1. In single cord blood bursts, the values of both gamma-to-beta and G gamma-to-A gamma ratios were spread over a large spectrum and further characterized by a continuous rather than a bimodal distribution. Morever, the G gamma-to-A gamma ratios demonstrated in single bursts appeared to be directly correlated with the respective gamma-to-beta ratios. These data suggest that both the gamma leads to beta and the G gamma leads to A gamma switches are mediated via mechanisms modulating the relative activities of the different genes in the non-alpha globin gene cluster rather than via selection of clones committed to the preferential synthesis of beta and A gamma globins. In contrast with the results obtained with cord blood, individual adult blood bursts synthesize a lower and hence relatively more uniform amount of gamma globin chains.

High-dose Ara-C (HiDAC) plus asparaginase in elderly patients with acute non-lymphocytic leukemia: a pilot multicentric study by the Italian Cooperative Group GIMEMA.

A multicentric prospective pilot study using three different schedules of high-dose Ara-C at dosage of 3 g/m2 every 12 hours during 3 h of infusion was undertaken by the Italian Cooperative Group GIMEMA in order: 1. to evaluate the safety and efficacy of such treatment in previously untreated ANLL patients more than 50 years old; 2. to investigate whether the addition of a standard maintenance treatment after consolidation with 4 courses of DAT (Daunorubicin + Ara-C + 6-Thioguanine) could improve the duration of complete remission (CR) and the proportion of long-term survival. Overall 43/125 evaluable patients (34.4%) achieved CR. 32/125 died during the induction phase, the remaining 50 patients (40%) failed to achieve CR. As for the toxicity, the most significant toxicity of all schedules was hematologic. No substantial neurological or cardiac toxicity was observed. The multivariated analysis of several pretreatment characteristics revealed that age more than 60 yr, male sex and presence of infections at diagnosis were the most significant adverse factors for achievement of CR. The median duration of DFS for all responders was 9 months, with relapse-free survival at 4 yr estimated at 29%. The addition of maintenance treatment to consolidated patients had no advantages in respect to the control group, even though the statistical analysis revealed a p = 0.058. However, because of the small number of randomized patients, no conclusions can be drawn concerning the importance of maintenance treatment.