Doxorubicin cytotoxic activity

In vitro studies with several tumor cell lines have shown vitamin C to enhance the cytotoxic activity of doxorubicin, cisplatin, paclitaxel, dacarbazine, 5-FU, and bleomycin. Vitamin C has also been shown to increase drug accumulation and to partially reverse vincristine resistance of human nonsmall-cell lung cancer cells. 

Venne, A., Li, S., Mandeville, R., Kabanov, A. V. Alakhov, V. (1996). Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. Cancer Res, 56,3626-3629. 

Doxorubicin treatment induced disruption of inner mitochondrial membrane potential Atjin, that precedes the nuclear signs of apoptosis (Decaudin et al. 1997). Both loss of At ini and apoptosis were prevented by Bcl-2 overexpression (Antoku et al. 1997, Decaudin et al. 1997), suggesting an important role for mitochondria in doxorubicin-induced apoptosis. Western blot analysis of Jurkat cell extracts indicated that caspases 2,3,4,6,7,8,9, and 10 were activated by doxorubicin (Gamen et al. 2000). Doxorubicin cytotoxicity was blocked by the protein synthesis inhibitor cycloheximide. 

Y. Ohya, K. Hirai and T. Ouchi, Synthesis and cytotoxic activity of doxorubicin boimd to poly(a-malic acid) via ester or amide bonds, Makromol. Chem., 193,1881-1887 (1992). 

In a study conducted by Liu et at, a doxorubicin (Dox)-carrier system was developed by electrostatic complexion of G4 PAMAM dendrimer with a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG, with lactose (LA) coupled at the distal end of the PEG chain [77]. A higher cumulative Dox release from LA-PEG-b-PSD/PAMAM complexes was observed at pH 6.5 compared to pH 7. In another study, a pH-sensitive dendrimer nanoparticle was prepared, where surface cationic charge of the PAMAM dendrimer was reduced to prevent opsonization in the systemic circulation [78]. Zwitterionic chitosan (ZWC), a chitosan derivative with a unique pH-sensitive charge profile, was used to modify the cationic surface of PAMAM dendrimers. A stable electrostatic complex between ZWC and PAMAM was formed at pH 7.4, where the PAMAM dendrimer surface was covered with ZWC. The results demonstrated that ZWC can mask the surface charge, which minimizes hemolytic and cytotoxic activities of PAMAM dendrimers. However, the complex dissociated due to the charge conversion at low pH, allowing PAMAM dendrimer charge to be exposed and facilitate its entrance into the cells. 

Selective Effect of Copolymers on Cytotoxic Activity of Doxorubicin against Drug Resistant Tumour Cells... 

To assess the mechanism by which Pluronic copolymers hypersensitise drug resistant tumour cells, we have analysed the effect of these compounds on the drug transport into and within the cells, as well as the drug interaction with DNA, which is known to be the target for cytotoxic activity of doxorubicin. ... 

Veronese FM, Schiavon O, Pasut G, Mendichi R, Andersson L, Tsirk A, Ford J, Wu G, Kneller S, Davies J, Duncan R (2005) PEG-doxorubicin conjugates influence of polymer structure on drug release, in vitro cytotoxicity, biodistribution, and antitumor activity. Bioconjug Chem 16 775-784... 

Bogdanovic G, Kojic V, Dordevic A, Canadanovic-Brunet J, Vojinovic-Miloradov M, Baltic VV (2004) Modulating activity of fullerol C60(OH)22 on doxorubicin-induced cytotoxicity. Toxicology In Vitro 18 629-637. 

The so-called self-immolative prodrugs are other relevant and intriguing examples as candidates for ADEPT (Fig. 8.17). Here, the primary bioactivation product is not the active agent, but an intermediate that breaks down spontaneously to liberate this active agent. Various cytotoxic drugs that bear an amino group were investigated, i. e., 4-[bis(2-chloroethyl)amino]aniline, actinomycin D, doxorubicin, and mitomycin C [206]. These were trans-... 

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