Modulation of Sensitivity to Mitoxantrone in Human Chronic Myeloid Leukemia Cells by the Antidepressant Sintamil

Chitnis, M.P.; Satyamoorthy, Kapaettu; Pradhan, S.G.; Sh, Advani

doi:10.1159/000226625

Cited by 8 publications

(3 citation statements)

References 12 publications

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“…Comparatively, samples 2, 3, 5, 7 and 10 show greater than 30% inhibition. Together with our earlier observations [5], it can be concluded that individual patient's CML cells exhibit variation in the cytotoxic action of mitoxantrone and this could indicate dif ferential response of patients in the clinics. This varia tion in cytotoxicity can be overcome with increasing concentrations of the drug.…”

Section: Discussionsupporting

confidence: 76%

“…We reported earlier that verapamil can enhance the cyto toxicity of adriamycin in CML cells [18], We have presented in this paper that verapamil also amelio rates mitoxantrone cytotoxicity in CML cells, thus demonstrating a causal relationship between them. Though verapamil alone demonstrated DNA biosyn thesis inhibition, it was reversible and not strictly dose dependent unlike that of mitoxantrone alone [5] and its combination with verapamil [unpubl. observa tions], Further, verapamil alone is not established as an anticancer drug.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of Mitoxantrone Cytotoxicity by Verapamil in Human Chronic Myeloid Leukemia Cells

et al. 1989

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Calcium channel-blocking agent verapamil has been established to be an effective drug to modulate the action of many anticancer drugs. In this study, we examined the effect of verapamil on the cytotoxicity of mitoxantrone in human chronic myeloid leukemia (CML) cells. Mitoxantrone alone exhibited dose-dependent inhibition of DNA biosynthesis in CML cells. The addition of verapamil (3.3 μM) enhanced the responsiveness of CML cells to mitoxantrone (1 μg/ml) cytotoxicity indicated by significant increased inhibition of thymidine incorporation (p <0.001). The present study demonstrates the possible efficacy of verapamil in the chemotherapy of CML with mitoxantrone.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Modulation of Mitoxantrone Cytotoxicity by Verapamil in Human Chronic Myeloid Leukemia Cells

et al. 1989

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“…The response to 1.0 and 10.0 nM PTX was very low, PTX at IOOjuM concentration was chosen for the subsequent studies. Sensitization of CML cells with PTX and DOX gave synergistic effect of DNA biosynthesis inhibition in 9 samples (sample numbers 1, 3,5,7,8,9,10,13,16) (19,20) and altered rheological properties of blood cells (21). Multiple drug resistant nature of tumor cell is associated with a decreased drug accumulation and an ATP-dependent active efflux of the drugs (22,23).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Doxorubicin Resistance by Pentoxifylline in Human Chronic Myeloid Leukemia Cells In Vitro

Viladkar¹,

Juvekar²,

Chitnis³

et al. 1991

Selective Cancer Therapeutics

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Doxorubicin (DOX) is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Pentoxifylline (PTX) is a non-toxic methylxanthine used clinically for the treatment of intermittent claudication. It is an active haemorheological agent, used for the treatment of defective microcirculation. In the present study, we employed PTX as a drug response modulator in combination with DOX to achieve increased cytotoxicity in human chronic myeloid leukemia (CML) cells. Inhibition of 3H-TdR incorporation was used as a measure of cytotoxicity. PTX at 100 microM concentration significantly (P less than 0.001) potentiated DOX-mediated DNA biosynthesis inhibition in CML cells in vitro. Significant synergistic inhibition was seen in 13 out of 22 CML samples. Decreased DOX accumulation is a characteristic feature of DOX resistant tumor cell lines. Drug accumulation studies demonstrated that PTX significantly (P less than 0.02) increased the intracellular accumulation of DOX in the CML cells. The enhanced DOX accumulation can be a mechanism of increased cytotoxicity by DOX-PTX combination.

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Sensitization of P388 Murine Leukemia Cells to Epirubicin Cytotoxicity by Reserpine

Viladkar

Chitnis²

1993

Cancer Biotherapy

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Reserpine, the crystalline active substance isolated from the Rauvolfia plant, produces a characteristic vasodepressor effect in hypertensive patients. Apart from its antihypertensive property, reserpine also possesses transquillising and vasodepressor action, hence it is employed as supportive therapy in the treatment of cardiac disorders. Doxorubicin is a potent anticancer agent, the use of which is limited by its cumulative dose-dependent cardiotoxicity. Epirubicin is a derivative of doxorubicin having more favourable therapeutic index than doxorubicin and possessing less hematologic and cardiac toxicity at comparable doses. The data presented in this paper show the effect of reserpine as a chemosensitizer, when used in combination with epirubicin on P388 murine leukemia cells sensitive (P388/S) and resistant to doxorubicin (P388/DOX) cells. Inhibition of 3H-TdR incorporation into DNA was used as an index of the cytotoxic effects of drug when used alone or in combination. The combination of reserpine (1 microM) and epirubicin (1.7, 8.6 and 17.2 microM) indicated a significant enhancement in the DNA biosynthesis inhibition in P388/S and P388/DOX cell lines. The most prominent feature of the multidrug-resistant cell is the reduced accumulation of the drug intracellularly. P388/DOX cells showed less accumulation of epirubicin in the cell as compared to that of the parental cell line. Further studies demonstrated that reserpine significantly enhanced the intracellular accumulation of epirubicin in both the cell lines. The nature of DNA damage caused by the combination of reserpine and epirubicin was irreversible when studied in P388/DOX cell line. The combination of reserpine (5mg/kg) and epirubicin (1mg/kg) significantly potentiated the antitumor activity of epirubicin in P388/DOX tumor bearing mice. These studies suggest that reserpine can be used as an adjuvant in the cancer chemotherapy to potentiate the antiproliferative activity of anticancer drugs.

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Modulation of Sensitivity to Mitoxantrone in Human Chronic Myeloid Leukemia Cells by the Antidepressant Sintamil

Cited by 8 publications

References 12 publications

Modulation of Mitoxantrone Cytotoxicity by Verapamil in Human Chronic Myeloid Leukemia Cells

Modulation of Mitoxantrone Cytotoxicity by Verapamil in Human Chronic Myeloid Leukemia Cells

Amelioration of Doxorubicin Resistance by Pentoxifylline in Human Chronic Myeloid Leukemia Cells In Vitro

Sensitization of P388 Murine Leukemia Cells to Epirubicin Cytotoxicity by Reserpine

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