Toxicity of ASTA Z 7557 (INN mafosfamide) to normal- and leukemic stem cells: Implications for autologous bone marrow transplantation

Summary The activity of the in vitro active cyclophosphamide metabolite ASTA Z 7557 against pluripotent hemo-poietic stem cells (CFU-S), in vitro myeloid precursor cells (CFU-C) and clonogenic leukemic cells (LCFU-S) was evaluated in a rat model for human acute myelocytic leukemia (BNML). LCFU-S were most sensitive (D₀ = 10.9 × 10^-6 M), followed by CFU-C (D₀ = 16.4 × 10^-6 M), while CFU-S were least sensitive (D₀ = 22.1 × 10^-6 M). Per cell population there were considerable variations in response when identical drug concentrations were tested in different experiments under the same standardized conditions.Furthermore, the concentration of leukemic cells in a normal marrow cell suspension appeared to correlate with the cytotoxic action of the drug against leukemia. A decreased cytotoxicity was already observed in mixtures containing 1 leukemic cell per 10 normal marrow cells.The implications of these findings in the BNML model for human autologous bone marrow transplantation are discussed.     

Experimental toxicology of ASTA Z 7557 (INN mafosfamide)

Summary The LD 50 of Z 7557 in mice was between 500 and 625 mg/kg after i.v. and around 2310 mg/kg after oral administration. The corresponding LD 10 was around 435 mg/kg (i.v.) or 1100–1250 mg/kg (p.o.), respectively.The LD 50 values in rats were in the range of 250–310 mg/kg after i.v. administration and around 1000–1250 mg/kg if given orally.With repeated daily i.v. injections only 70% of the daily dose contributed to lethality. A second administration of Z 7557 to rats after reversal of all toxic signs from the first administration induced the same symptoms and degree of toxicity as the initial injection.Reversible myelosuppression was the predominant feature of toxicity in mice and rats, but at equimolar doses this myelotoxicity was less than half that of cyclophosphamide (CP). First signs of immunosuppression were seen only at 100 mg/kg i.v.No severe urotoxicity was observed in rats with single i.v. doses up to 192 mg/kg. This might be due to the fast and complete renal excretion of the thiol moiety of Z 7557, whereas the activated oxazaphosphorine component occurred in the urine only to a much smaller amount, as could be shown by a pilot pharmacokinetic study.In conclusion, Z 7557 appeared to have an overall tolerance in rats and mice similar to cyclophosphamide but was clearly less toxic with respect to the bone marrow, the immune system and the urinary tract.     

Antineoplastic activity of ASTA Z 7557 (NSC-345842, INN mafosfamide) on transplantable murine tumors

Summary The antitumor activity of ASTA Z 7557, a stabilized primary metabolite of cyclophosphamide, was evaluated in comparison with cyclophosphamide (CP) against different rodent tumor systems. At equimolar doses, which corresponded in mg/kg to the optimal doses of each compound, Z 7557 showed a higher therapeutic activity than CP when both drugs were administered intraperitoneally (ip) during 5 consecutive days. The drug remained active against a P388 subline totally resistant to CP, but to a much lesser extent. The ipimplanted B16 melanoma was highly sensitive to 100 and 50 mg/kg administered during 9 consecutive days: an increase in lifespan (ILS) of 244% was produced and 5 mice out of 10 were cured. This treatment administered against Lewis lung carcinoma (LL) transplanted intravenously (iv) induced an ILS of 179% and 3 mice out of 10 survived on day 60. This effect was slightly inferior to that produced by 50 mg/kg of CP, but is balanced by the number of long-term survivors recorded after administration of low doses of Z 7557. When mice bearing the subcutaneously (sc) implanted colon 38 (C38) tumor were treated with 200 mg/kg on days 2 and 9, the tumor growth was inhibited by 83% in comparison to the control mice. The wide range of activity of Z 7557, its stability and its different chemical reactivity as compared to CP appear to justify interest in this activated oxazaphosphorine.     

Comparative effects of ASTA Z 7557 (INN mafosfamide) and cyclophosphamide on hematopoiesis in mice

Summary Acute effects of ASTA Z 7557 and Cyclophosphamide (Cy) on pluripotential (CFU-S), granulocytic (CFU-C), early erythroid (BFU-E) and late erythroid (CFU-E) progenitor cells in the bone marrow, as well as on RBC and WBC, were compared in F₁ (CBA × C 57 BL) female mice. Dose-survival curves of both agents for CFU-S and CFU-C were found to be exponential, indicating that the effects of the drugs have no cell cycle dependency. At equimolar doses, marrow CFU-S and CFU-C contents appeared to decrease more rapidly with increasing doses of ASTA Z 7557 than with those of Cy. After a single dose of 200 mg/kg of each drug (= 50% LD₁₀), there was greater initial suppression of CFU-S, CFU-C, BFU-E and CFU-E in the Cy-treated animals than in ASTA Z 7557-treated mice. In both groups, however, the WBC had their nadir on Day 3 after treatment, followed by a return to normal by Day 8. In ASTA Z 7557-treated animals, the recovery of CFU-S, CFU-C and BFU-E was also completed by Day 8 after treatment. In Cy-treated mice, however, complete recovery of these cells was achieved on Day 15. Results indicate quantitative rather than qualitative differences between the marrow toxicities of ASTA Z 7557 and Cy in mice. Quantitative differences could be due to different pharmacokinetic properties of the agents, since Cy is excreted in partially unmetabolized form, and it might be that this inactive part of the agent grew with increasing drug doses.     

Inhibition of human B lymphocyte differentiation by a stable metabolite of cyclophosphamide (ASTA Z 7557, INN mafosfamide)

Summary We have evaluated the immunosuppressive effect of a new stable derivative of cyclophosphamide (ASTA Z 7557) on human lymphocyte immunoglobulin biosynthesis in vitro. When graded amounts of the drug are added to lymphocyte cultures stimulated with the helper T cell-dependent activator (PWM), a marked inhibition of B cell proliferation and differentiation occurs. Lymph node cells are particularly sensitive to the drug, while splenocytes are relatively resistant. The agent exerts only a minor effect on immunoglobulin synthesis triggered by a direct B cell stimulant (S. paratyphi bacteria).     

Comparative in vitro cytotoxicity of cyclophosphamide,its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide)

Summary Cyclophosphamide (CPA), the most commonly used alkylating agent in the treatment of a wide variety of hematologic and solid tumors, requires oxidation by hepatic microsomal enzymes to its active alkylating species. A number of alternative methods exist to simulate the in vitro cytotoxicity of CPA against animal and human tumors, including the co-incubation of CPA with the S-9 fraction of rat liver homogenates (S-9) and the use of either 4-hydroperoxy CPA (a stabilized form of a major blood-borne metabolite of CPA), phosphoramide mustard (PM, considered to be the ultimate intracellular alkylating metabolite of CPA), or ASTA Z 7557 [4-(2-sulfonatoethylthio)-CPA, a new oxazaphosphorine compound which after dissolution undergoes rapid spontaneous hydrolysis in vitro with liberation of 4-hydroxy-CPA]. Using a human tumor clonogenic assay (HTCA) we have quantitated the median molar inhibitory dose 50 (ID₅₀) concentrations of S-9 activated-CPA, 4-hydroperoxy-CPA, PM, and ASTA Z 7557 against 107 previously untreated tumors, as well as determining the in vitro biological stability of the former three CPA metabolite preparations. 4-Hydroperoxy-CPA proved the most consistently cytotoxic (median molar ID₅₀=5.77#x00D7;10^–5M) compound, followed by ASTA Z 7557, S-9 activated-CPA and PM in that order. Of additional interest S-9 activated CPA and PM proved relatively unstable biologically when frozen at -120°C, whereas 4-hydroperoxy-CPA lost none of its cytotoxicity over a 36 day period during freezing. On the basis of these data 4-hydroperoxy-CPA appears the compound of choice for use in vitro to evaluate the activity that CPA is likely to express clinically against solid tumors. Since 4-hydroperoxy-CPA is not available for clinical use, ASTA Z 7557, which was slightly less cytotoxic to ovarian cancers and a wide variety of other tumors in the HTCA, appears an attractive agent to develop further clinically, especially for regional chemotherapy (e.g., intraperitoneal and intra-arterial treatment) of solid tumors.     

Effect of ASTA Z 7557 (INN mafosfamide) a precursor of 4-hydroxy-cyclophosphamide on human T-lymphocytes' Fc-receptors and immunoregulatory functions

Summary The precursor ASTA Z 7557 of the in vivo active metabolite 4-hydroxy-cyclophosphamide (4OH-Cy) of cyclophosphamide (Cy) was tested for selective effects on human T-lymphocytes' Fc-receptor expession and certain immunoregulatory functions. It has been found that ASTA Z 7557 does not alter the expression of Fc-F or Fc-I-receptor on the T-cell membrane nor does it exhibit differential toxicity for either T-cell sub-population. PWM-induced B-cell proliferation is inhibited by ASTA Z 7557, whereas B-cells' Ig-synthesis as well as ConA-driven T-cell proliferation is only blocked with higher doses of the reagent. Final concentrations above 1 g/ml may therefore abrogate ConA-induction of suppressor T-lymphocytes. Already ConA-activated suppressor cells of PWM-driven B-cell cultures, however, are not inhibited even with high doses of ASTA Z 7557.     

ASTA Z 7557 (INN mafosfamide) for the in vitro treatment of human leukemic bone marrows

Summary The in vitro treatment of leukemic bone marrows, collected during complete remission, aims at eliminating residual blast cells prior to freezing and preservation, while sparing normal hematopoietic stem cells.We report our experience on the activity of ASTA Z 7557 on human leukemic (CFU-L) and normal hematopoietic stem cells.The sensitivity of human leukemic and normal progenitor cells (CFU-c), detected in semi-solid media cultures, is similar. However, pre-CFUc progenitors detected in long term marrow cultures are much less sensitive to ASTA Z 7557. Therefore autologous bone marrow transplantation can successfully be done with pretreated marrows containing 5±5% residual CFUc. The wide range of stem cells sensitivity to ASTA Z 7557 justify the predetermination of the optimal dose of drug for incubation prior to marrow collection for each individual patient. Our preliminary clinical experience is exposed.     

Antineoplastic activity of ASTA Z 7557 (INN mafosfamide) in transplanted and autochthonous experimental rodent tumors

Summary The antineoplastic activities of ASTA Z 7557 and cyclophosphamide (CPA) were compared in advanced transplanted AKR lymphoma by determining the optimal dose using single dose and twofold applications. Autochthonous DMBA-induced leukemias and MNU-induced mammary carcinomas were treated with fractionated doses over 3 and 5 weeks, respectively. In the respective optimal dosages ASTA Z 7557 exhibited an antitumor effect comparable to that of CPA in all three models. The results obtained by treatment of the autochthonous models indicate that Z 7557 seems to have advantages over CPA in the treatment of malignancies with impaired bone marrow function as for instance acute leukemias and in fractionated dose schedules.     

Macromolecular DNA-damage in murine and human leukemic and lymphoid cells after in vitro exposure to ASTA Z 7557 (INN mafosfamide)

Summary Cyclophosphamide (CPA) is widely used against leukemic and lymphoproliferative diseases, but in vitro studies on response to this agent so far have been limited to instable derivatives with poor galenic properties. ASTA Z 7557 is a newly synthesized activated cyclophosphamide that circumvents the need for hepatic activation and has good stability. The critical cytotoxic lesions after exposure to bifunctional alkylating agents presumably are DNA interstrand crosslinks (ISC). We have, therefore, examined the formation and apparent removal of ISC after in vitro treatment with ASTA Z 7557 by use of the highly sensitive alkaline elution technique. Survival of murine L1210 cells was determined after 1 hour in vitro exposure with a D 37 value of 5.7 g/ml (from the initial shoulder part of the survival curve) and a Do value of 1.5 g/ml (from the exponential part of the curve). Previous labelling of L1210 cells by ¹²⁵IUdR simplified the alkaline elution procedure but there was some cytotoxicity of the radiochemical itself with a reduction of cloning efficiency from 77% to 61 %. The maximum of ISC was observed at 6 h after initiation of treatment with much of the damage apparently removed at 24 h. The simultaneous presence of DNA single strand breaks (SSB), however, confounds the analysis of DNA damage at 24 h and early cytolysis and unaided death of human lymphocytes often preclude the analysis of macromolecular damage at this time. Human peripheral blood cells isolated from patients with leukemic or lymphoproliferative diseases showed a remarkable heterogeneity with regard to the formation of ISC at 3 h. Thus, analysis of macromolecular damage may become an additional prognostic factor for response to CPA beyond the morphologic classification of these diseases.     

贵州省首例半相合骨髓移植治疗急性白血病报告

目的 探讨半相合骨髓移植治疗急性白血病的疗效.方法 对1例男性47岁急性髓系白血病M2型患者采用半相合骨髓移植.预处理方案采用改良的BU/CY方案;GVHD的预防采用ATG+CSA+MMF +MTX方案;移植方式采用骨髓加外周血移植.结果 移植后19 d患者造血功能重建.移植后第30天、90天、180天行STR-DNA...     

Preclinical evaluation of toxicity and therapeutic efficacy of a stabilized cytostatic metabolite of cyclophosphamide (ASTA Z 7557, INN mafosfamide)

Summary ASTA Z 7557 is a stabilized cytostatic metabolite of cyclophosphamide which forms crystals at room temperature and releases 4-OH-cyclophosphamide in aqueous solution. The LD_50/30 in mice after push injection is 417 mg/kg, after fractionated administration (q 6 hours × 4) 794 mg/kg. Daily treatment times 5 gives a LD_50/30 value of 200 mg/kg. Depression of nucleated bone marrow cells and of leukocytes in the peripheral blood is observed after treatment. Recovery is slow. This holds true for push and fractionated administration. ASTA Z 7557 is a powerful cytostatic drug for treatment of an Ehrlich ascites tumor, a Lewis lung and a mammary carcinoma. Of two human tumor xenografts a malignant amelanotic melanoma responded with slight growth delay, whereas a gastric cancer did not.     

Antiproliferative activity of 2-[N,N-bis-2-chloroethyl}-amino]-4-[2-sulfonato-ethylthio]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide cyclohexamine (ASIA Z 7557, INN mafosfamide) against human and murine tumor cells in vitro

Summary The ability of ASTA Z 7557 to inhibit colony formation in vitro by 6 human tumor cell lines and 3 methylcholanthrene-induced murine fibrosarcomas was compared to that of cyclophosphamide, 4-hydroperoxy-cyclophosphamide, BCNU, cisplatin, mitomycin C, doxorubicin, and 5-fluorouracil, as a function of dose, and duration of exposure. All drugs except cyclophosphamide were active in a dose and time dependent manner against all cell lines. ASTA Z 7557 and 4-hydroperoxy-cyclophosphamide at equimolar concentrations had similar antiproliferative activities. The stabilities of ASTA Z 7557 and 4-hydroperoxy-cyclophosphamide as measured by cytotoxic activity remaining after incubation at various times at 37° in complete tissue culture medium containing 10% fetal calf serum were identical. At initial concentrations of 20 M, cytotoxic activity of both compounds began to decline after two hours of incubation and all activity was lost after 24 hours of incubation. In vitro, ASTA Z 7557 produced, at least, additive cytotoxic activity with cisplatin, the combination of cisplatin plus doxorubicin, and human lymphoblastoid interferon.     

A comparative study of therapeutic activity,myelotoxicity and DNA damage in the bone marrow of mice after cyclophosphamide and ASTA Z 7557 (INN mafosfamide)

Summary This study compares the two oxazaphosphorine compounds ASTA Z 7557 (AZ) and cyclophosphamide (CP) in their therapeutic activity as well as in their myelotoxicity and DNA damage being induced after a single intraperitoneal injection. Therapeutic activity was determined towards methylnitrosourea-induced rat mammary carcinomas in vivo and in vitro, resulting in comparable efficacy of both compounds at their optimal doses, respectively, with the sensitivity of individual tumors being reflected by the degree of inhibition of ³H-thymidine uptake of these cells in vitro.Myelotoxicity was measured as inhibition of pluripotent (CFU-S) and macrophage-granulocyte committed (CFU-C) stem cells together with the extent of single strand breaks and DNA-DNA interstrand crosslinks in murine bone marrow. At equimolar base AZ was found to induce a higher level of DNA damage than CP in the bone marrow of mice 16 hours after a single intraperitoneal injection. Both compounds depressed the pluripotent stem cell compartment of the bone marrow to a similar extent, whereas AZ was significantly less toxic to the granulocyte cell lineage.Abbreviations AZ ASTA Z 7557; 2-[N,N,bis-(2-chloroethyl)-amino]-4-(2-sulphonato-ethylthio)-tetrahydro-2H-1,3,2, oxazaphosphorine-2-oxide - CP Cyclophosphamide; 2-[N,N,bis-(2-chloroethyl)-amino]-1,3,2-oxazaphosporine-2-oxide - CFU-C Granulocyte-committed stem cells - CFU-S Pluripotent stem cells - BCNU 1,3-bis(2-chloroethyl)-1-nitrosourea - MNU N-methyl-N-nitrosourea - Mesna 2-mercaptoethanesulphonate     

Chemical characterization of ASTA Z 7557 (INN mafosfamide,CIS-4-sulfoethylthio-cyclophosphamide), a stable derivative of 4-hydroxy-cyclophosphamide

Summary The primary metabolite of cyclophosphamide (CP, 1), i.e. 4-hydroxy-CP 2, has high pharmacological activity, but it is a very unstable compound. Chemical approaches to the stabilization involved in the substitution of the hydroxy group at the C 4-position, especially by a sulfoalkylthio-moiety. Within this new class of compounds ASTA Z 7557 (2-(bis-(2-chloroethyl))-amino-cis-4-((2-sulfoethyl)-thio)-tetrahydro-2H-1,3,2-oxazaphosphorine-r-2-oxide cyclohexylamine salt, i.e. cis-4-sulfoethylthio-CP, cis-13) was chosen for further evaluation. Cis-13 was synthesized by condensation of compound 2 and 2-mercapto-ethanesulfonic acid cyclohexylamine salt 14 in aqueous acetone yielding the cis-isomer with high stereoselectivity. It is a white crystalline powder, m.p. 126–134°C, stable at room temperature, with a solubility of 16% in water. The stereochemistry was confirmed by NMR-data and X-ray diffraction. In 0.07 M phosphate buffer at pH 7 and 37°C cis-13 isomerizes to the epimer trans-13, equilibrating at a cis-trans-ratio of 59 to 41 within less than 5 minutes. Simultaneously a rapid initial hydrolysis occurs to 2 and 14 followed by a time period with lower degradation due to the decomposition of 2. The rate of release of 2 increases with decreasing concentration and especially by addition of an oxidant. It could be retarded by addition of the corresponding thiol mesna, sodium 2-mercapto-ethanesulfonate 15, or of another thiol. In the presence of 3-mercapto-propane sulfonate 13 yielded 4-(3-sulfopropyl)thio-CP17.With changing pH values from 2 to 9, the lowest hydrolytic speed was observed at pH 4.0 to 4.3. For clinical use cis-13 is prepared as a lyophilisate containing additional sodium citrate buffer to guarantee this optimal pH value.     

骨髓间充质干细胞治疗小型猪急性心肌梗死的实验研究

目的：研究自体骨髓间充质干细胞（mesenchymal stem cell，MSC）经冠脉内注射治疗急性心肌梗死的效果。方法：先以球囊阻塞法制成小型猪急性心肌梗死模型。取骨髓体外培养并扩增MSC，标记后经冠脉注入，1个月后核素心肌显像检测相对心肌梗死面积、心肌灌注评分和射血分数、经导管检测左室收缩压（LVSP）、左室舒张末期压（LVEDP）、压力升高最大速率（LV＋dp／dtmax）和压力下降最大速率（LV—dp／dtmin）。并以NOGA电机械标测细胞移植前和移植后心肌缺血面积，免疫荧光法分析MSC的植入和分化情况。结果：和对照组相比，细胞治疗组射血分数[（44．1±4．3）％ vs （39．0±5．2）％，P〈0．05]、心肌灌注评分[（30．0±5．3）vs（41.8±8．8），P〈0．01]、相对心肌梗死面积[（28．6±4．7）％ vs （33．5±3．4）％，P〈0．05]、LV＋dp／dtmax[（1818±117）mm Hg／s vs （1611±115）mm Hg／s，P〈0．01，mmHg=0．133kPa]、LV—dp／dtmin[（1801±89）mmHg／s vs （1618±66）mmHg／s，P〈0．01]均显著增加，LVEDP[（9．4±1．7）mmHg vs（12．6±2．8）mmHg，P〈0．05]显著降低。病理检查发现细胞移植术后1月，原梗死心肌相关区域即可见带MSC标记物的新生心肌和血管，且该部分心肌表达阳性的肌凝蛋白重链、连接蛋白43、平滑肌肌动蛋白和Ⅷ因子相关抗原。结论：MSC体外培养扩增后经冠脉植入可在心肌梗死小型猪心肌梗死相关区域分化为具有生理功能的新生心肌和血管组织，可改善急性心肌梗死猪的心功能。     

Efficacy and toxicity of 4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (ASTA Z 7557, INN mafosfamide) after intraperitoneal administration to mice

Summary 4-(2-sulfonatoethylthio)-cyclophosphamide cyclohexylamine salt (AZ; ASTA Z 7557) is a cyclophosphamide (CP) analog designed to be without acute bladder toxicity and to undergo spontaneous activation yielding phosphoramide mustard (PM). Studies in murine systems with intraperitoneal (i.p.) administration suggest that AZ may have a therapeutic index favorable to CP without an associated risk of bladder toxicity. Pericapsular hepatic fibrosis after i.p. administration suggests that regional AZ therapy may cause local toxicity. Further study of this compound, especially with intravenous (i.v.) administration, will be of interest.     

A phase I clinical and pharmacological profile of dacarbazine with autologous bone marrow transplantation in patients with solid tumors

Summary Dacarbazine (DTIC) is a chemotherapy drug which has antitumor activity at standard doses, exhibits a steep dose-response effect in vitro, and is associated with relatively few non-hematologic toxicities. These characteristics suggest a potential role for this drug in bone marrow transplant preparative regimens. To pursue this hypothesis, 16 patients with refractory solid tumors were enrolled in a phase I study of single agent DTIC to determine the dose of DTIC requiring bone marrow reinfusion and to define the dose-limiting toxicity and maximum tolerated dose when given with autologous bone marrow rescue. Pharmacokinetics were evaluated at the 4394 mg/m² dose level. The marrow requiring dose was 2000 mg/m² when given as a single intravenous (IV) infusion. The extramyeloid dose-limiting toxicity of DTIC was hypotension, with the maximum tolerated dose of DTIC being 3380 mg/m² when given with bone marrow transplantation (BMT). Other toxicities were transient and tolerable. At 4394 mg/m² of DTIC, plasma concentrations declined biexponentially with a terminal half-life of 3 hours. The mean clearance was 10.6 L/hr/m² with a volume of distribution at steady state of 37.5 L/m² and a mean maximum plasma concentration of 150 mcg/ml. One patient with melanoma developed a partial response of short duration after receiving 2600 mg/m² of DTIC. Dacarbazine can be significantly dose escalated with an acceptable toxicity profile, when given with BMT. Future trials should focus on the addition of this drug to current BMT preparative regimens used for the treatment of patients with lymphoma.     

Autologous transplantation of bone marrow mononuclear cells improved heart function after myocardial infarction

AIM: To investigate whether autologous transplantation of adult stem cells could improve post-infarcted heart function. METHODS: Bone marrow mononuclear cells (MNCs) were isolated from adult rabbits‘ tibias after coronary ligation. These cells were exposed to 5-azacytidine 10 μmol/L for 24 h on the third day of culture. After being labeled with bromodeoxyuridine (BrdU), the cells were auto-transplanted into bordering zone of the infarcted area at 2 weeks after injury. The animals were killed at 3 days, 2 weeks, 1 month, and 2 months after transplantation,respectively. The left ventricular functions, capillary density, and cardiac nerve density were measured and the differentiation of the engrafted cells was determined by immunostaining. RESULTS: BrdU-labeled MNCs were well aligned with the host cardiomyocytes. Parts of them were incorporated into capillary and arteriolar vessel wails. In addition to inducing angiogenic ligands (basic fibroblast growth factor, vascular endothelial growth factor) and imflammation cytokines (interleukin 1-β) during the early period of MNCs implantation, MNCs induced 2.0-fold increase in capillary density as well. Moreover, GAP43-positive and TH-positive nerve density were markedly higher in the MNCs-treated groups than that in the non-treated hearts. Left ventricular ejection fraction,LV dp/dtmax, and LV-dp/dtmax were 47 %, 67 %, and 55 % in MNCs-treated heart respectively, which was higher than that of the control heart, whereas left ventricular end-diastolic volume, left ventricular end-diastolic diameter,and left ventricular end-diastolic pressure were 45 %, 22 %, and 50 % respectively in MNCs-treated heart, which was lower than that of the control heart at 2 months after cell transplantation. CONCLUSION: Autologous transplantation of MNCs induced angiogenesis and nerve sprouting and improved left ventricular diastolic function.     

骨髓活检在急性非淋巴细胞白血病化疗前、后的应用

应用骨髓活检对15例初治ANLL化疗前、后骨髓病理变化进行定量分析。结果表明:骨髓活检标本对确定骨髓内细胞分布、间质变化、骨髓细胞增生程度和判断化疗效果均较骨髓穿刺涂片优越,二者相互配合可以比较全面地反映骨髓的病理变化。