ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01586.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

SUMMARYFifty two patients (aged 15–57 years) with primarily failed and relapsed acute myelogenous (AML) or lymphoblastic leukemia (ALL) and with high‐grade non‐Hodgkin's lymphoma (NHL) have been treated with intermediate dose cytosine arabinoside. Ara‐C (1 g/m2q 12 h × 12) with 3 d of m‐AMSA, 115 mg/m2daily was given to 18 patients, with daunorubicin (3 patients) 45 mg/m2daily for 3 days to 3 patients and in 14 patients 1 day of m‐AMSA (115 mg/m2) was administered.In 17 patients ara‐C was combined with VP16.213 120 mg/m2i v. on day 1 and 7, m‐AMSA 115 mg/m2i.v. on day 1 and 7 and prednisone 60 mg/m2orally on days 1–7, these patients received methotrexate 10 mg/m2intrathecally on day 1. Thirty three patients obtained a complete remission (AML 18/24, ALL 7/9, NHL 8/18).17 patients received consolidation treatment with 1–3 courses comprising 4 d of ara‐C (3 g/m2q 12 h × 8). in 9 patients combined with m‐AMSA 115 mg/m2i.v. on day 5 and in 8 patients with VP16.213 120 mg/m2on day 1 and 5, m‐AMSA 115 mg/m2on day 1 and 5 and prednisone 60 mg/m2orally days 1–5 and methotrexate 10 mg/m2intrathecally on day 1. Three patients underwent allogeneic bone marrow transplantation, all other patients received no further treatment.Median remission duration was 3 months for those patients who received no treatment after remission induction. Five patients who received consolidation treatment relapsed after 4 months (2 ALL), 6 months (NHL), 9 months (AML) and 16 months (AML). Thirteen patients still are in remission at 2+ ‐ 21+ months.In addition to vomiting, fever, skin rashes, conjunctivitis and myalgia toxicity included diarrhoea in 35.8 per cent of patients and 10 patients developed diffuse interstitial pneumonia without clear cause and probably due to ara‐C administration. Fifty‐eight septicemic episodes were observed, in 65% caused by Streptococcus viridans. The pancytopenic period ranged from 16–25 days (median 21 days) after the remission induction and 14–21 days (median 19 days) after the consolidation course.Intermediate dose ara‐C is active in primary refractory and relapsed acute leukemia and lymphoblastic non‐Hodgkin's lymphoma. Side effects are acceptable although interstitial lung‐i

ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01587.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

ABSTRACTClinical resistance to ara‐C is dose and schedule dependent. Patients refractory to or who have relapsed on combinations of drugs which include standard doses of ara‐C (100–200 mg/m2daily for 5 to 7 days) can be induced into clinical remissions with high dose ara‐C (HiDAC). The interaction between HiDAC and asparaginase is schedule‐dependent; pharmacologic synergy and an improvement in the therapeutic index occurring with sequential HiDAC→Asparaginase. This combination has been applied in clinical trial: ara‐C 3 g/m2as a 3 hr IV infusion was given every 12 hrs for 4 doses. At the end of the 4th infusion, 6000 IU/m2asparaginase was given IM. This therapy was given on days 1 and 8. Refractory/ relapsed patients had a 68% complete remission rate. Treatment of 49 patients with previously untreated ANLL was associated with an 80% and 40% complete remission rate in patients60 years of age, respectively. Median time to complete remission for both age groups was 30 days. The lower complete remission rate in older patients reflects higher induction deaths (ID) (50%), not innate drug resistance. Laboratory investigations have focused on the biochemical pharmacology of HiDAC in an attempt to explain the unique therapeutic utility of this mode of drug administration. These data suggest that human leukemia cells transport ara‐C across the cell membrane relatively less efficiently than experimental leukemia cells. The systemic metabolite of ara‐C, ara‐U, may also influence the drug's effect. In the murine leukemia L5178Y, both in vitro and in vivo, high concentrations of ara‐U are cytostatic in S‐phase. the phase of the cell cycle wherein ara‐C cytotoxicity is increased. In vivo, high concentrations of ara‐U also retard systemic deamination of ara‐C as well as its renal excretion. These features increase the terminal half‐life of HiDAC in the plasma and thus prolong cellular exposure to the drug. The interactions between ara‐U and ara‐C th

ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01588.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

SUMMARYPharmacokinetic studies of ara‐C in plasma are reviewed. The value of monitoring ara‐C in plasma is limited, because ara‐C is an inactive prodrug, and has to be phosphorylated to ara‐CTP intracellularly to excert its activity. Therefore, the pharmacokinetics of ara‐CTP in leukemic cells was studied. The differences between the pharmacokinetics of ara‐C in plasma and ara‐CTP in leukemic cells in terms of elimination rates and heterogeneity are important and there seems to be only poor correlation between the two. This is the rational for attempts to correlate the pharmacokinetics of cellular ara‐CTP to clinical effect of ara‐C treatment. The accumulation of ara‐CTP seems to be saturated during high‐dose ara‐C treatment. As a consequence, the duration of infusion is a more important determinant of the efficacy than the dose in high‐dose ara‐C treatment. This should be considered in design of high‐d

ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01589.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

ABSTRACTThe pharmacology of 1‐β‐D‐arabinofuranosylcytosine 5′‐triphosphate (ara‐CTP) has been studied in the circulating leukemic blasts of patients with refractory leukemia during therapy with high doses of single‐agent ara‐C. Cellular ara‐CTP was analyzed by high‐pressure liquid chromatography. The median trough concentrations of ara‐CTP in blasts of patients who responded to intermittent high‐dose ara‐C (3 g/m2× 4–12 doses) was 196 μM, whereas 75 μM was the lowest trough ara‐CTP concentration that discriminated between complete remission and treatment failure (p=0.03). The median steady state ara‐CTP concentrations in the blasts of patients who responded to a high dose continuous infusion protocol (2 doses of 3 g/m2every 12 hr followed by a continuous infusion of 330–3000 mg/m2× 4 d) were clustered between 79 and 206 μM. The values of treatment failures were predominantly outside this range (p<0.005). These results suggest that the optimal concentration range for intracellular ara‐CTP in the treatment o

ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01590.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY

摘要:

SUMMARYEight patients with AML of unfavourable prognosis were treated with combinations of low doses of ara‐C, retinoic acid, vitamin D3 and alpha‐interferon. 2 complete remissions and 3 partial responses were achieved. The good response in this patient group, together with the observation that 3 of the responders (1 complete remission) had no prior marrow hypoplasia, are suggestive of mechanisms of action that are separate from those in conventional chemotherapy. Possible alternatives are the induction of differentiation of leukemic cells, stimulation of normal stem cells, a slowly active selective cytotoxicity on leukemic stem cells with only minor side effects on normal stem cells, or combinations of these mechani

ISSN:0036-553X    

DOI:10.1111/j.1600-0609.1986.tb01591.x

出版商:Blackwell Publishing Ltd    

年代:1986

数据来源: WILEY