1‐Methyl‐3‐propyl‐7‐butylxanthine, a Novel Biochemical Modulator, Enhances Therapeutic Efficacy of Adriamycin

  title={1‐Methyl‐3‐propyl‐7‐butylxanthine, a Novel Biochemical Modulator, Enhances Therapeutic Efficacy of Adriamycin},
  author={Yasuyuki Sadzuka and Ayano Iwazaki and Tomomi Sugiyama and Takayuki Sawanishi and Ken‐ichi Miyamoto},
  journal={Japanese Journal of Cancer Research : Gann},
  pages={228 - 234}
We have screened xanthine derivatives for activity as novel biochemical modulators by assay of their inhibitory effect on adriamycin efflux from tumor cells. Strong inhibition of adriamycin efflux was shown by some xanthine derivatives with various alkyl or oxoalkyl substituents at the 1‐, 3‐ and 7‐positions. 1‐Methyl‐3‐propyl‐7‐butylxanthine (XT‐77), which had the greatest inhibitory effect on adriamycin efflux in vitro among the compounds tested, potentiated adriamycin‐induced antitumor… 
Effects of 1‐Methyl‐3‐propyl‐7‐butylxanthine (MPBX) on Idarubicin‐induced Antitumor Activity and Bone Marrow Suppression
The combination of MPBX with IDA is expected to be useful for leukemia chemotherapy because it increased the antitumor activity and decreased the bone marrow suppression in P388 tumor‐bearing mice.
Enhanced efficacy of 1-methyl-3-propyl-7-butylxanthine on the antitumor activity of doxorubicin against doxorubicin-resistant P388 leukemia.
In vitro, the facilitated DOX influx and suppressed efflux by MPBX in both types of tumor cells were similar, suggesting that MPBx acts on the same site in both type of cells.
Effects of xanthine derivatives on the influx and efflux of doxorubicin in P388 and DOX-resistant P388 leukemia cells.
The results indicated that the resistance of P388/DOX might depend on the over-expression of P-gp, and that XT-141 inhibited DOX efflux through its interaction with P- gp, and it is suspected thatXT-141 is a useful biochemical modulator of DOX in DOX-resistant tumors with over- expression ofP-gp in addition inDOX-sensitive tumors.
Inhibitory effects of caffeine analogues on neoplastic transformation: structure-activity relationship.
It is indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent.
Increased effects of MPDAX, a novel xanthine derivative, on antitumor activity of doxorubicin.
MPDAX, acting via nucleoside transporters, increases the DOX-induced antitumor activity toward many tumor types and is an useful biochemical modulator.
Modulation of doxorubicin sensitivity by a novel organic compound, oxalyl bis (N-phenyl) hydroxamic acid on acetyl aminofluorene-induced preneoplastic hepatocytes.
Two novel hydroxamic acid derivatives are reported that increase doxorubicin sensitivity and on P-glycoprotein (P-gp) in acetyl amino fluorene (AAF) induced preneoplastic hepatocytes in vitro and decrease the dose related side effect of doxorbicin.
Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine hemangiosarcoma cell lines.
The data suggest that caffeine and theophylline have anticancer effects and can improve the treatment effect in canine hemangiosarcoma patients and both drugs may enhance doxorubicin-induced cytotoxicity by inhibiting ATM/ATR kinases.
Why the xanthine derivatives are used to study of P-glycoprotein-mediated multidrug resistance in L1210/VCR line cells.
This paper shows that some xanthine derivatives (pentoxifylline and its derivatives) depress P-glycoprotein (P-gp) mediated multidrug resistance of the mouse leukemic cells, and confirms this usefulness of long side substituted xanthines as biochemical modulators.
Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea.
Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities and results suggest that theanine selectively moderates the IDa-induced toxicities.
Nutrient Signaling – Protein Kinase to Transcriptional Activation
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Effects of Methylxanthine Derivatives on Adriamycin Concentration and Antitumor Activity
The metabolism of caffeine may weaken its effect as a biochemical modulator, and that pentoxifylline and theobromine would be of value as biochemical modulators of adriamycin.
Correlation Between Hydrophobicity of N‐Alkylxanthine Derivatives and their Biological Activities on Guinea‐pig Isolated Tracheal Smooth Muscle
Findings suggest that the cAMP PDE inhibitory activity of N‐alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.
Caffeine Modulates the Antitumor Activity and Toxic Side Effects of Adriamycin
The results suggest that the combination of caffeine with adriamycin can significantly increase the in vivo antitumor activity of this agent without increasing its side effects.
Selective Bronchodilators from 1‐(5′‐Oxohexyl)xanthines
It is indicated that N 3 alkylation is important for the selectivity for tracheal muscle, while the introduction of long alkyl chains such as n‐butyl and n‐pentyl groups at the N 3 and N 7 positions diminished the potency for the right atrium in guinea‐pigs.
Structure-activity relationship in N3-alkyl-xanthine derivatives.
The present study indicated that butylxanthine may be a new candidate as a bronchodilator, however, clinical studies have to be carried out to compare its efficacy and adverse effects with those of existing bron chodilators such as theophylline.
Mechanism of caffeine modulation of the antitumor activity of adriamycin.
The effect of caffeine on ADR concentration in the cell plays an important role in the mechanism by which caffeine enhances ADR antitumor activity, and in vitro, ADR efflux from Ehrlich ascites carcinoma cells was significantly inhibited by exposure to caffeine.
Effects of xanthine derivatives on lipolysis and on adenosine 3',5'-monophosphate phosphodiesterase activity.
Close correlation between these two activities strongly indicates that the lipolytic activity of the xanthine derivatives is a result of inhibition of cyclic AMP phosphodiesterase.
Bronchodilator activity of xanthine derivatives substituted with functional groups at the 1- or 7-position.
It is indicated that the substitutions with none or low polar functional groups at the 1-position could improve the selectivity and duration of the bronchodilator effects of xanthines.
Effects of alkyl substituents of xanthine on phosphodiesterase isoenzymes.
The results suggested that the potency of the inhibitory activity of xanthine derivatives on PDE isoenzymes is not dependent simply upon their hydrophobicity but upon change in the affinity for the active sites on Pde isoenZymes by the introduction of the alkyl group at particular positions of the xanthin skeleton.
Effects of alkyl substitutions of xanthine skeleton on bronchodilation.
Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.