Sequence-, time- and dose-dependent synergism of methotrexate and 6-mercaptopurine in malignant human T-lymphoblasts.

Methotrexate (MTX) and 6-mercaptopurine (6MP) are common drugs in the oral maintenance therapy of acute lymphoblastic leukemia (ALL). On the basis of their biochemical effects on cell metabolism, a sequence-dependent synergism might be anticipated. In order to investigate this hypothesis, MOLT-4 human malignant T-lymphoblasts were incubated with various concentrations of MTX. The time at which maximal increase of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) levels was found correlated with the concentrations of MTX used. Determination of aminoimidazolecarboxamide ribonucleoside monophosphate (AICAR) levels and labeled glycine incorporation into purine metabolites revealed an incomplete inhibition of purine de novo synthesis after incubation with 0.02 microM MTX, and a complete inhibition with 0.2 microM MTX. After prolonged periods of incubation, glutamine exhaustion of the medium caused inhibition of purine de novo synthesis in MTX-untreated cells, with a concomitant increase of PRPP levels. Addition of glutamine to the medium prevented this phenomenon. The increased availability of PRPP after pretreatment with MTX can be used for enhanced intracellular incorporation of hypoxanthine and 6MP in their respective nucleotides. The time- and dose-dependent effects of MTX on PRPP levels correlated with the enhanced incorporation of hypoxanthine and 6MP. The data presented in this study demonstrate that a synergistic action of the combination of MTX and 6MP can be anticipated in malignant lymphoblasts with an active purine de novo synthesis depending on the concentration of MTX and on the time and sequence of administration of both drugs.

A ceruloplasmina como enzima marcadora de atividade neoplásica maligna / The ceruloplasmin with enzyme activity maligna neoplasm

Os autores estudaram os níveis de atividade oxidásica da cerulopasmina sérica em ratos machos da linhagem isogênica U inoculados com um sarcoma singênico. Hiperceruloplasminemia estatisticamente significativa foi observada em todas as fases de crescimento tumoral. Valores normais de cerulopasmina foram obtidos unicamente após a 1ª dose de ciclofosfamida (100 mg/Kg, por via intraperitoneal). A subseqüente administraçäo semanal da droga näo bloqueou o reaparecimento da hiperceruloplasminemia nos animais portadores de sarcoma. Ratos normais tratados pela ciclofosfamida, de acordo com o mesmo esquema, apresentaram queda na atividade enzimática após a 1ª dose. Os autores concluem que a hiperceruloplasminemia sugere a presença latente de células neoplásicas viáveis e pode servir como um teste bioquímico para monitorizar o processo maligno

Effect of cyclophosphamide on serum ceruloplasmin oxidase activity in sarcoma bearing rats.

High levels of serum ceruloplasmin oxidase activity were detected in U strain isogenic male rats bearing a syngeneic sarcoma in all phases of tumoral evolution. Normal levels of ceruloplasmin were only observed after a single i.p. dose of cyclophosphamide (100 mg/kg). However subsequent weekly administration of the drug did not prevent the return of hyperceruloplasminemia in the tumor hosts. Normal rats treated similarly with cyclophosphamide presented a fall in the enzyme activity after the 1st dose.

Changes induced by Ehrlich ascites carcinoma in hepatic fumarase and aconitase activities.

Ehrlich ascites carcinoma induced significant changes in liver fumarase (activation) and aconitase (inhibition). A significant increase in hepatic fumarase specific activity was also observed in mice inoculated with Ehrlich ascites fluid after centrifugation of cells (EAF). Hepatic aconitase was not significantly influenced by EAF.

The influence of lithium on serum ceruloplasmin.

Serum ceruloplasmin oxidase activity did not change in mice treated orally for 120 days with Li2CO3 (0.58 mEq/kg/day). After a single i.p. injection of LiCl (20 mEq/kg), a significant activation of ceruloplasmin was observed.