Akira Kiue

Synthesis and structure–activity analysis of novel dihydropyridine derivatives to overcome multidrug resistance

The structure activity relationships were studied on newly synthesized 1,4-dihydropyridine derivatives possessing a 1-pentyl group at the 4-position, and 3-pyridylpropylester was found to be one of the effective fragments for overcoming P-glycoprotein mediated multidrug-resistance (MDR) in cultured human cancer cells, in vitro. 3-Pyridylpropylester was also found to be one of the effective fragments for increasing the life span of P-glycoprotein overexpressing MDR P388 leukemia-bearing mice, in vivo. All compounds had weak calcium antagonistic activities, but there appeared no relationship between MDR reversing effect and calcium antagonistic activity.

Irsogladine is a potent inhibitor of angiogenesis

We describe a novel inhibitor of angiogenesis, Irsogladine, an anti‐ulcer drug. Irsogladine inhibited plasminogen activator synthesis of, and tube formation by, human microvascular endothelial cells in type 1 collagen gel treated with an angiogenic growth factor, EGF. Furthermore, Irsogladine administered orally significantly inhibited in vivo angiogenesis in mice. Irsogladine may be useful in the treatment of diseases associated with angiogenesis.

Molecular analysis of mechanisms regulating drug sensitivity and the development of new chemotherapy strategies for genitourinary carcinomas.

A bstractThe emergence of drug-resistant tumors during treatment remains one of the major obstacles in cancer chemotherapy. Overexpression of P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene or multidrug resistance-associated protein (MRP) (or both) and decreased expression of DNA topoisomerase II are responsible for expression of the multidrug resistance (MDR) phenotype. The expression of P-glycoprotein is also often observed in untreated cancers showing spontaneous MDR, such as renal cell carcinoma. Regarding cisplatin resistance, decreased cisplatin accumulation, an increase in cisplatin detoxification by glutathione-related enzymes or metallothionein (or both), and increased repair of DNA damage are all considered to play an important role. The combination of reversal agents targeting such drug resistance markers may be a way to improve the outcome of chemotherapy. Regarding the presently available reversal agents, however, clinically relevant chemosensitizing doses cannot be given to humans without inducing significant toxicity. The development of new agents that reverse drug resistance without causing significant toxicity and their clinical application based on the mechanisms regulating drug sensitivity may therefore be a potentially effective new treatment strategy for genitourinary carcinomas.

Newly synthesized dihydropyridine derivatives as modulators of P-Glycoprotein-mediated multidrug resistance

Newly synthesized 1,4-dihydropyridine derivatives possessing alkyl chains at the 4-position screened whether they could overcome P-glycoprotein-mediated multidrug resistance in cultured cancer cells and also leukemia-bearing animals. Of these derivatives, some could overcome drug resistance to doxorubicin and vincristine in multidrug resistant human cancer cell lines. Combined administration of vincristine and some of the derivatives significantly increased the life span of P-glycoprotein overexpressing multidrug-resistant P388 leukemia-bearing mice. The calcium antagonistic activities, an undesirable effects, were weaker than that of verapamil. These results suggested that the introduction of alkyl groups at the 4-position were effective for both overcoming multidrug resistance and reducing the calcium antagonistic activity.

Reversal by a Dihydropyridine Derivative of Non-P-Glycoprotein-Mediated Multidrug Resistance in Etoposide-Resistant Human Prostatic Cancer Cell Line

PURPOSE We have isolated etoposide-resistant prostatic cancer cell lines, P/VP10 and P/VP20, to investigate the multidrug resistance (MDR) mechanism and to find MDR reversal agents. MATERIALS AND METHODS We examined expression of MDR-related genes and screened reversal agents of MDR in P/VP20 cells. RESULTS These cells demonstrated a non-P-glycoprotein (P-gp)-mediated MDR phenotype with overexpression of MDR-associated protein (MRP) mRNA due to MRP DNA amplification. A 1,4-dihydropyridine derivative, bis(4-pyridylmethyl)4-[2-(3-methyl-5,6- dihydro-1,4-dithiinyl)]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar boxylate (NIK250), was found to overcome MDR in P/VP20 cells. CONCLUSIONS NIK250 might be useful in reversing MDR, which often develops during chemotherapy of advanced or hormone-resistant prostatic cancer.

Reversal by Two Dihydropyridine Compounds of Resistance to Multiple Anticancer Agents in Mouse P388 Leukemia in vivo and in vitro

We investigated whether two representative 1,4‐dihydropyridine derivatives, NK‐250 and NK‐252, could potentiate the antitumor activity of multiple anticancer agents including vincristine (VCR), vinblastine, vindesine and actinomycin D in drug‐resistant tumor cells and their parental drug‐sensitive tumor cells. NK‐250 and NK‐252 at 5–10 μM almost completely reversed VCR resistance in cultured VCR‐resistant P388/VCR cells derived from the mouse drug‐sensitive P388/S leukemia cell line and also potentiated the cytocidal activity of VCR in drug‐sensitive P388/S cells. NK‐250 and NK‐252 at 1–10 μM inhibited the photoaffinity labeling by [3H]azidopine of the cell‐surface 170,000‐molecular‐weight P‐glycoprotein. In chemotherapeutic experiments with leukemia‐bearing mice, NK‐250 or NK‐252 was orally administered in combination with different drugs of the MDR phenotype administered intraperitoneally. The antitumor activity of the various combinations was found to be augmented in mice bearing P388/S‐ and P388/VCR‐leukemia. Among the combinations examined, the combination of NK‐250 and VCR was the most effective. These two 1,4‐dihydropyridines, NK‐250 and NK‐252, are unique compounds because they were effective not only in circumventing the drug resistance, but also in potentiating the action of antitumor drugs against drug‐sensitive tumors.