Effect of diethyldithiocarbamate on toxicity of doxorubicin, cyclophosphamide and cis-diamminedichloroplatinum (II) on mice haemopoietic progenitor cells

Pannacciulli, I; Lerza, Roberto; Bogliolo, G; Saviane, A

doi:10.1038/bjc.1989.74

Cited by 26 publications

(8 citation statements)

References 19 publications

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“…But high-dose chemotherapy for optimal antitumour effect often cannot be contemplated because of the toxicity on proliferating normal cells. DXN, like several other anticancer drugs, has toxic effects on cells of the haematopoietic system resulting in peripheral blood leucopenia, neutropenia and thrombocytopenia (Pannacciulli et al 1989). For reasons described earlier, the use of G-CSF and GM-CSF can also be disadvantageous.…”

Section: Discussionmentioning

confidence: 97%

“…We therefore hypothesised that DA could be effective in alleviating the adverse haematological effects, and augmenting the antitumour efficacy of commonly used anticancer drugs. To test the first part of this hypothesis, the present work has been conducted in Swiss mice using doxorubicin, a potent anticancer agent having profound haematotoxicity (Pannacciulli et al 1989), as the myelosuppressive agent.…”

Section: Introductionmentioning

confidence: 99%

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Modulatory Effect of Dopamine on Doxorubicin-induced Myelosuppression

Ray¹,

Lakshmi²,

Deb³

et al. 2001

Comparative Haematology International

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Bone marrow suppression is a dose-limiting toxicity of anticancer drugs. We have investigated in this study whether dopamine (DA), a catecholamine neurotransmitter, could alleviate the haematotoxicity of doxorubicin (DXN), an established anticancer drug having profound myelotoxicity. DA was injected intraperitoneally at a dose of 50 mg/kg/day for five consecutive days in Swiss mice. The animals received a single intravenous injection of DXN (25 mg/kg) 24h after last injection of DA. DXN caused an immediate and sharp fall in total leucocyte, neutrophil, lymphocyte and platelet counts in peripheral blood, and nucleated cells in femur and spleen. DA treatment before DXN substantially reduced the degree and duration of these abnormalities, and also mediated a significant rise in the number of cells of granulocyte and erythroid lineage in the spleen. DA-pretreated mice showed early recovery of megakaryocytes (MK) and their precursors (SAChE+ cells), and stimulation of pulmonary MK. Thrombopoiesis, assessed in terms of incorporation of 35 S by platelets, was stimulated in DA-treated mice. Moreover, DA pretreatment partially protected the day 12 colonyforming unit spleen (CFU-S 12 ) from the lethal effects of DXN, and substantially reduced the mortality of the treated animals. The results demonstrate protection by DA against the myelosuppressive effect of DXN.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Modulatory Effect of Dopamine on Doxorubicin-induced Myelosuppression

Ray¹,

Lakshmi²,

Deb³

et al. 2001

Comparative Haematology International

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“…Tetraethylthiuramdisulfide (disulfiram; DTDS) and its major metabolite, diethyldithiocarbamate (DDTC), protect rodents against the damaging effects of alkylating carcinogens and some antineoplastic drugs [1][2][3][4]. It was found that DTDS administered for 2 h before N-nitrosodiethylamine (NDEA) decreases DNA fragmentation and DNA alkylation in both liver and esophageal mucosa [5].…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFκB c-fos/c-jun, and p53 proteins

et al. 1998

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Prolinedithiocarbamate (PDTC) and diethyldithiocarbamate (DDTC) are cancer chemopreventive agents and can be biotransformed to prolinethiuramdisulfide (PTDS) and tetraethylthiuramdisulfide (disulfiram; DTDS), respectively. We found that the reactive metabolites PTDS and DTDS induced apoptosis after G1/S arrest. Phosphorylation of cyclin E, inhibition of cyclin-dependent kinase 2 activity, and degradation of cyclin E were found in human hepatoma Hep G2 cells during apoptosis. Moreover, PTDS and DTDS decreased the level of bcl-2 but increased the level of p53. In contrast, PDTC, DDTC, and ammonium dithiocarbamate (ADTC) did not induce apoptosis; rather they led to the induction of p53 and p21 followed by G1/S arrest. PDTC, DDTC, and ADTC also arrested cells in G1 phase. We then examined the effects of PTDS and DTDS on the signal transduction mechanisms leading to apoptosis. Although the transcription factors NFkappaB and AP-1 cooperatively decreased their DNA-binding activities to kappaB and 12-O-tetradecanoylphorbol-13-acetate-responsive elements, respectively, and p53 increased DNA-binding activity in the early stage but decreased it in the latter stage after treatment with PTDS, when the human Hep G2 cells were undergoing apoptosis. In summary, our results indicated that (i) PTDS and DTDS induced apoptosis and G1/S arrest mediated by p53, whereas PDTC, DDTC, and ADTC induced p53-dependent p21 expression leading to G1/S arrest; (ii) PDTC, DDTC, and ADTC induced p21/KIP1/CIP1 expression in a p53-dependent pathway leading to G1/S arrest; and (iii) NFkappaB, AP-1, and bcl-2 were downregulated during PTDS- and DTDS-induced apoptosis. These results suggested that PTDS and DTDS induced p53-dependent apoptosis, whereas PDTC, DDTC, and ADTC induced G1/S arrest. Apoptosis is regulated by the modulation of intracellular effectors such as NFkappaB, AP-1, and bcl-2 and activation of p53 in early stages.

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“…Metal dithiocarbamates are now available for medicinal or for diagnostic use as radiopharmaceuticals and for diagnostic kit (17). Number of reports on antifungal (5,21), antibacterial (4,22,24,27,28), antialkylation (9,19), anticancer and apoptosis inducing activity (1) of the metal dithiocarbamate complexes of the mixed ligands …”

mentioning

confidence: 99%