Preventive effects of interleukin 1 ? for ACNU-induced myelosuppression in malignant brain tumors: the experimental and preliminary clinical studies

Abstract

The effect of recombinant human interleukin 1 beta (rHuIL-1 beta) on myelosuppression induced by 3-[(4-amino-2-methyl-5-pyrimidynyl)methyl]-1-(2-chloroethyl)-1-nit rosourea hydrochloride (ACNU) was studied. In in vivo study using BALB/c mice, pretreatment with 1 microgram/mouse of rHuIL-1 beta as a single intraperitoneal (i.p.) injection had a significant preventive effect on thrombocytopenia as well as granulocytopenia induced by ACNU at an intravenous dose of 60 mg/kg. Facilitated recovery by rHuIL-1 beta administered seven days after injection of high-dose ACNU was also observed. Experimental combination immunochemotherapy with high-dose ACNU and rHuIL-1 beta was performed in nude mice inoculated with human glioblastoma subcutaneously. The elongation of the survival time of the tumor bearing nude mice was also observed in combined use of high dose ACNU with rHuIL-1 beta. Seven patients with malignant brain tumors received intravenous 2.5-3 mg/kg ACNU. All patients were subcutaneously injected with 2 x 10(4)-U or more rHuIL-1 beta twice a week or daily. The mean nadir of leukocyte, granulocyte, and thrombocyte counts of the 7 patients received 2.5-3 mg/kg ACNU were significantly higher than in matched historical controls. In combination with rHuIL-1 beta, it may be possible to use chemotherapeutic agents at a relatively high dose.

Individual adjuvant therapy for malignant gliomas based on O6-methylguanine-DNA methyltransferase messenger RNA quantitation by real-time reverse-transcription polymerase chain-reaction

“…Some authors, including us, have reported that MGMT expression is closely correlated with the clinical or experimental resistance of brain tumors to ACNU (6,7,10). The expression level in DNA measured by PCR may not be always correlated to the enzyme activity.…”

“…Drug-resistance genes are some of the most important elements of tumors themselves in determining drug-resistance and O 6 -methylguanine-DNA methyltransferase (MGMT) is a drug-resistance gene for nitrosourea (6,7). The cross-linking of Individual adjuvant therapy for malignant gliomas based on O 6 -methylguanine-DNA methyltransferase messenger RNA quantitation by real-time reverse-transcription polymerase chain-reaction double-stranded DNA by alkylating agents is inhibited by the cellular DNA-repair protein MGMT.…”

“…Furthermore, MGMT plays a major role in interfering with the effect of TMZ (9). We performed individual adjuvant therapy (IAT) that was individualized based on the results of reverse transcription-polymerase chain reaction (RT-PCR) for MGMT to treat malignant gliomas in a non-randomized trial (7). Previously, in order to improve IAT, we applied real-time quantitative RT-PCR to the quantitation of MGMT mRNA in IAT for malignant gliomas (10,11).…”

Machine-Learning Approach for Modeling Myelosuppression Attributed to Nimustine Hydrochloride

“…9 In conventional research on myelosuppression, mean and box-whisker plots (as shown in Figs 1A and 1B) are used to show blood count nadirthe point at which the patient's blood count is lowest during treatment-and severity of blood count decrease. [10][11][12] A blood cell count nadir is detected by examining the minima in the graph of the transition curve. In daily clinical data, it is difficult to detect the minimum points.…”