Myeloblastic leukaemia

It is indicated in GI tract carcinoma, acute myeloblastic leukaemia, bronchogenic, breast and ovarian carcinoma, soft tissue and bone sarcomas, malignant lymphoma primary management of nonmetastatic bladder carcinoma (intravesical administration), Wilm s tumor and neuroblastoma. 

The introduction of an azido substituent on the C-2 position of cytosine arabinoside (ara-C) (149) or adenosine arabinoside (ara-A) (154) has been found to confer favourable properties to these antimetabolites. Ara-C, one of the most effective drugs for the treatment of human acute myeloblastic leukaemia [176], is subject to rapid metabolic deamination, by deoxycytid-ine deaminase, to the inactive uridine derivative ara-U (152) Scheme 3.5), and the drug has a half-life of approximately 12 minutes in man [177]. Efforts to circumvent this problem by modifying the 2 -arah/ o-position led... 

The clinical course of polycythaemia rubra vera (PRV) is marked by a high risk of thrombotic complications and a variable incidence of transformation to myelofibrosis or acute myeloblastic leukaemia. The object of treatment is to minimise the risk of thrombosis and to prevent transformation. The following are used. 

Fassas A, Buffels R, Anagnostopoulos A, Gacos E, Vadikolia C, Haloudis P, Kaloyannidis P. Safety and early efficacy assessment of liposomal daunorubicin (DaunoXome) in adults with refractory or relapsed acute myeloblastic leukaemia a phase I-II study. Br J Haematol 2002 116(2) 308-15. 

Finally, there is evidence that cannabidiol can induce apoptosis in cultures of at least some types of human cancer cell HL-60 myeloblastic leukaemia cells and... 

Cahn JY, Labopin M, Sierra J, et al. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplant (EBMT). Br J Haematol 2000 110 308-314. 

The biochemical pharmacology of the MTX analogues (VIII.268)-(VIII.270) has been investigated also by McGuire et al. [380]. In assays using purified DHFR from K562 human myeloblastic leukaemia cells and CCRF-CEM lymphoblastic leukaemia cells, IC50 values of 2-4 nM for... 

Another enzyme that has been implicated in the metabolism of vincristine in acute myeloblastic leukaemia (AML) cells is myeloperoxidase. The fact that AML is resistant to vincristine has been related to the presence of mieloperoxidase, which is able to catalize the vincristine s oxidative breakdown [198, 199]. 

Azacytidine (500) was reduced with sodium borohydride in hexamethyl phosphoramide followed by acidification to dihydro-5-azacytidine (501). The deuterated derivative (502) was made similarly from sodium borodeu-teride, Scheme 5.118.) [652, 653]. 5-Azacytidine (500) is an antitumour agent, effective against human acute myeloblastic leukaemia and acute lymphoblastic leukaemia. However, it is unstable in aqueous solution, so the stable dihydro derivative (501) was made. This is 30 x less potent than (500), but has the same spectrum of activity however it has a superior therapeutic index and is better able to cross the blood-brain barrier. It may be a prodrug for 5-azacytidine [654-658],... 

Buick RN, Till JE, McCulloch EA (1977) Colony assay for proliferative blast cells circulating in myeloblastic leukaemia. Lancet 1 862-863... 

Carcinostatic agents with redifferentiating properties include 5-bromo-deoxyuridine, which initiates differentiation in neuroblastoma cells (Schubert and Jacob, 1970), and cytarabine (see p. 126), which stimulates in vitro maturation of human myeloblastic leukaemia cells to become normal macrophages or granulocytes (Takeda 1981). 

The retention of activity is expected since a substituent here would not fundamentally interfere with DNA binding according to the models proposed for the intercalation complex. Rubidazone, the benzhydrazone (A -benzoylhydrazone) of daunomycin [229], has been shown to be at least equivalent to daunomycin in the treatment of acute myeloblastic leukaemia [230] and in animal tests is claimed to be less cardiotoxic than adriamycin yet equivalent in potency [231]. Recently Gabbay has reported studies on a group of compounds (98-102) which have an amino substituent at C-13 [86]. All compounds bind to DNA in a similar manner to daunomycin but activity in vivo is much reduced as would be expected. It is significant that the water-soluble a ycones (101) and (102) retain activity in in vitro tests, although activity is lower than for the ycosidic analogues. This emphasises that the daunosamine unit can be replaced. 

The sulphate of this alkaloid has been used mainly for the treatment of Hodgkin s disease, reticulum cell sarcomas, lymphosarcomas, monocytic leukaemias, choriocarcinomas, and mammary and ovary carcinomas [66-70a]. It has been used also in combination with vincristine for the treatment of acute lymphocytic and myeloblastic leukaemias in children [71]. Toxic... 

Doxorubicin [10 ] 1982 Acute lymphoblastic leukaemia, Acute myeloblastic leukaemia, Wilms tumour, neuroblastoma Soft tissue and bone sarcomas Breast carcinoma Ovarian carcinoma Transitional cell bladder carcinoma Thyroid carcinoma Gastric carcinoma Hodgkin s disease Malignant lymphoma Bronchogenic carcinoma 60-75 mg/m IV 21 day intervals as monotherapy 40-60mg/m2 IV 21-28day intervals in combination therapy Max recommended cumulative dose 450-500mg/m ... 

On the other hand, hydroquinone (3 pmol/L) prevented the staurosporine-induced apoptosis of HL-60 and the IL-3-dependent murine myeloblastic (32D) cell line it also prevented apoptosis of the 32D cells observed in the absence of IL-3. The myeloperoxidase inhibitor indomethacin opposed the effect of hydroquinone on staurosporine-induced apoptosis of HL-60 cells (Hazel et al., 1995, 1996b). Pretreatment of human leukaemia cells ML-1 with buthionine sulfoximine (100 pmol/L for 24 h), in order to decrease their glutathione content, increased the susceptibility of these cells to hydroquinone-induced inhibition of differentiation caused by phorbol acetate pretreatment with l,2-dithiole-3-thione, which induces reduced glutathione synthesis, prevented the differentiation inhibition of hydroquinone. Treatment of DBA/2 mice with 1,2-dithiole-3-thione, which increased the activity of quinone reductase of bone-marrow stromal cells by 50%, decreased the susceptibility of these cells towards hydroquinone (Trush et al., 1996). 

B-ALL B-CLL Hairy cell leukaemia Waldenstrom macro-globulinaemia Myeloblasts in CGL Lymphoblasts in CGL... 

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