Tumors, drug-resistant

Raviv, Y., Pollard, H. B., Bruggemann, E. P., Pastan, I., Gottesman, M. M., Photosensitized labeling of a functional multidrug transporter in living drug-resistant tumor cells, J. Biol. Chem. 1990, 265, 3975-3980. 

Early administration of effective combination chemotherapy at a time of low tumor burden should increase the likelihood of cure and minimize emergence of drug-resistant tumor cell clones. Combination regimens have historically been more effective than single agent chemotherapy (Table 61-1). 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

Smyth MJ, Drasovskis E, Sutton VR, Johnstone RW (1998) The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sd USA 95 7024-7029... 

Anthoney DA, Mcllwrath AJ, Gallagher WM, Edlin ARM, Brown R. Microsatellite instability, apoptosis and loss of p53 function in drug resistant tumor cells. Cancer Res 1996 56 1374—1381. 

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to 6-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy. 

Hamada H, Tsuruo T. Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. Proc Natl Acad Sci U S A 1986 83(20) 7785-7789. 

Tsuruo T, Iida H, Kitatani Y, et al. Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. Cancer Res 1984 44(10) 4303 4307. 

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. 

MacDiarmid JA et al (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotech 27 643-651... 

In 2002, it was found that a 2-diflurobenzoyl paclitaxel analog (60d) exhibited comparable activity with paclitaxel, are best in C-2 mono- and di-substituted benzoyl analogs and better than 9a and 9b in paclitaxel-resistant HCT-116/VM46 cancer cell lines. It was also reported that some 2-debenzoyloxy-2a-benzamido docetaxel analogs were comparably cytotoxic with paclitaxel toward some drug-resistant tumor cell lines. 

Shimizu K, Asai T, Fuse C, Sadzuka Y, Sonobe T, Ogino Taki T, Tanaka T, Oku N (2005) Applicability of anti-neovascular therapy to drug-resistant tumor Suppression of drug-resistant P388 tumor growth with neovessel-targeted liposomal adriamycin. Int J Pharm 296 133-141... 

Agrawal, M., Abraham, f., Balis, F.M., Edgerly, M., Stein, W.D., Bates, S., Fojo, T, and Chen, C.C. (2003) Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clinical Cancer Research, 9 (2), 650-656. 

DiOC6 (3) is rapidly removed from the cells that have active efflux pump (P glycoprotein), such as stem cells or multi-drug resistant tumor cells, which may simulate collapse of AW,. 

Epothilones, isolated from the mycobacterium Sorangium cellulosum in 1996, are a new class of cytotoxic macrolides that are especially effective against drug-resistant tumor cell lines by the same mechanism as the taxoids. The structural feature of epothilones (Fig. 1) includes a 16-membered lactone ring, p-hydroxyl carbonyl units and cw-epoxide on the macrocyclic ring, and a thiazole unit as the side chain. 

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