Tumor cells drug resistance, reversal

Vincristine resistance has been studied in Chinese hamster ovary cell lines cells resistant to vincristine also are resistant to vinblastine and vindesine. Suggestions were made that, in cells with relatively low levels of drug resistance, at least two prominent mechanisms of resistance can occur (22). In the first instance, cellular resistance may be attributable to membrane alterations that are reversible, functionally, by treatment with verapamil. In the second, resistance has been postulated to be due to an altered sensitivity of tubulin to the effects of the drugs the primary basis for postulating an altered interaction with tubulin was that a subgroup of cells resistant to vincristine showed enhanced sensitivity to taxol, a drug that can stabilize microtubules. It should be emphasized that differential sensitivities of tubulins from different tumor cells to the effects of vincristine or vinblastine has been proposed as a basis for the susceptibilities of cells to the cytotoxic effects of such drugs (23). Differences have been described in the electrophoretic patterns for tubulins obtained from vin-... 

Fig. 1. Microenvironmental factors and the invasive process. The primary tumor is a heterogeneous mix of cell populations, further diversified by gradients of blood-borne nutrients, oxygen, and drugs. Hypoxia contributes to treatment resistance, upregulates pro-angiogenic and pro-invasive molecules, and helps to maintain cancer stem-like cell populations. Tumor cells may undergo epithelial-to-mesenchymal transition (EMT), enter blood vessels, and disseminate to distant sites where they extravasate, invade, and colonize the tissues. Once established, the cells may undergo the reverse program (mesen-chymal-to-epithelial transition, MET) and proliferate to form metastases, the major reason for treatment failure.

Kobayashi, H., Dorai, T., Holland, J.F. and Ohnuma, T. (1994) Reversal of drug sensitivity in multidrug-resistant tumor cells by an MDR1 (PGYl)ribozyme. Cancer Res., 54, 1271-1275. 

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. 

Pourtier-Manzanedo A, Boesch D, Loor F. FK-506 (fujimycin) reverses the multidrug resistance of tumor cells in vitro. Anticancer Drugs 1991 2(3) 279-283. 

Welwistatin also inhibits cell proliferation with reversible depletion of cellular microtubules in ovarian carcinoma cells and A-10 vascular smooth muscle cells by inhibiting the polymerization of tubulin, but it does not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP [8]. Due to the cytotoxicity associated with the inhibition of tubulin polymerization, which is the main mechanism of action of antitumor drugs such as vincristine and vinblastine, and because P-gp-overexpressing cells show virtually no resistance to welwistatin due to its MDR reversal properties, this natural product could be a good candidate in the chemotherapy of drug-resistant tumors. 

DSC and NMR techniques were used to study the type and degree of interaction between drug and bilayer. The results were compared with those from experiments on the ability of the compounds to reverse MDR in vitro in resistant tumor cell lines. In the DSC experiments, the change in phase transition, Tt and enthalpy, AH, was recorded. Some of the results are summarized in Table 5.15, together with the MDR-reversing activities and PKC inhibitory activity. 

Hochlowski, J. E., Mullally, M. M, Spanton, S G., Whittem, D. N., Hill, P., and McAlpine, J. B. (1993) 5-N-Acetylardeemm, a novel heterocyclic compound which reverses multiple drug resistance in tumor cells II. Isolation and elucidation of the structure of 5-N-acetylardeemin and two congeners. J Antibiotics 46,380-386. 

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