Effects of 1‐Methyl‐3‐propyl‐7‐butylxanthine (MPBX) on Idarubicin‐induced Antitumor Activity and Bone Marrow Suppression

Abstract

The effects of 1-methyl-3-propyl-7-butylxanthine (MPBX), a xanthine derivative, on idarubicin (IDA)-induced antitumor activity against P388 leukemia cells (P388) and bone marrow suppression were examined. In P388 tumor-bearing mice, the combination of MPBX with IDA increased the antitumor activity of IDA. The IDA concentration in the tumors in the MPBX combination group increased by 2.0-fold compared to the level in the IDA-alone group. On the other hand, as regards IDA-induced bone marrow suppression, the combination of MPBX with IDA reduced the decrease in the bone marrow cell number by 30% compared to that in the IDA-alone group. In addition, the IDA concentration in the bone marrow cells was decreased by the combination of MPBX with IDA. An in vitro experiment showed that MPBX facilitated IDA influx and suppressed IDA efflux in P388 cells. In conclusion, the combination of MPBX with IDA increased the antitumor activity and decreased the bone marrow suppression. Therefore, we expect that the combination of MPBX with IDA will be useful for leukemia chemotherapy.Key words: 1-Methyl-3-propyl-7-butylxanthine -Idarubicin -Antitumor activity -Adverse reaction -Bone marrow suppression Chemotherapeutic agents play important roles in cancer therapy, but there are many problems, including side effects and the appearance of resistant cells. Studies of biochemical modulation to enhance the antitumor activity and suppress side effects by means of combination treatment with non-antitumor drugs are being carried out and could improve the efficacy of cancer chemotherapy.In our previous study, we confirmed that caffeine, a xanthine derivative, increases the antitumor activity induced by doxorubicin (DOX) against Ehrlich ascites carcinoma cells through suppression of DOX efflux.1-3) Furthermore, it was confirmed that this inhibitory effect on DOX efflux is correlated with the structure of xanthine derivatives.4) 1-Methyl-3-propyl-7-butylxanthine (MPBX, Fig. 1) significantly suppresses DOX efflux and increases antitumor activity induced by DOX. 5,6) On the other hand, idarubicin (IDA), a newly synthesized anthracycline used in the treatment of acute myeloblastic leukemia, 7-10) can cause suppression of bone marrow cells and death in clinical use. Because IDA-induced antitumor activity is exerted on leukemia cells in the bone marrow and blood, it is impossible to separate the antitumor activity and side effects, so the use of IDA is limited. Most biochemical modulators increase the antitumor activity with a concomitant increase in side toxicity. But we confirmed that MPBX decreases the cardiotoxicity induced by DOX in addition to enhancing the antitumor activity of DOX. 11)Thus, the combination of MPBX with IDA might allow the separation of antitumor activity and bone marrow suppression.In this study, we examined the effects of MPBX on the antitumor activity and bone marrow suppression induced by IDA. The results indicate that combination treatment with IDA and MPBX could be useful for the treatment of leukemia. MATERIALS AND ME...

Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus

“…Besides AMI, there are also a great amount of drugs that could be used to prevent IDAR-evoked cytotoxicity. For example, dexrazoxane is approved by FDA to prevent cardiotoxicity and genomic damage caused by IDAR [ 41 ]; Vitamin C could be used as protective agents against DNA damage in normal cells in the presence of IDAR [ 43 ]; Theanine and 1-methyl-3-propyl-7-butylxanthine could increase the antitumor activity of IDAR and ameliorates its toxicities [ 46 ]. Grape seed proanthocyanidin extract can ameliorate the toxic effects of IDAR by upregulating the expression of Bcl-2 [ 47 ]; Other agents such as Vitamin E, Coenzyme Q10, carnitine, probucol, carvedilol, et al also have the ability to reduce the cardiotoxicity caused by IDAR [ 48 ].…”

Inhibitory effects of caffeine analogues on neoplastic transformation: structure-activity relationship

“…Tumor promoter-induced neoplastic transformation was also inhibited by caffeine treatment (11). 1,3-Dimethylxanthine (theophylline) and 1-methyl-3-propyl-7-butylxanthine (xanthine 77) were proposed to be potential anticancer drugs especially in combination with other chemotherapeutic drugs (15)(16)(17)(18). Some xanthine analogues containing methyl groups were also reported to enhance the killing of p53deficient cells (19).…”

ANTITUMOR ACTIVITY OF SOME NEW 1,3,8TRISUBSTITUTED PURINE-2,6-DIONES AND 1,3,6TRISUBSTITUTED THIAZOLO[2,3-f]PURINE-2,4DIONES

“…Recently, we reported 1,8-disubstituted purine-2,6-diones as potent analgesic and anti-inflammatory agents through adenosine receptor antagonism [9][10][11] and also 3,6-disubstituted thiazolo[2,3f]purine-2,4-diones as potent analgesic and anti-inflammatory 12 . Caffeine and xanthine derivatives increase the concentration of doxorubicin concentration in Ehrlich ascites carcinoma cells and P388 leukemia cells, through suppression of the doxorubicin efflux from cells in-vitro [13][14][15][16] .…”