Cancer cell selectivity

S. O. Freytag, K. R. Rogulski, D. L. Paielli, J. D. Gilbert, and J. H. Kim, A novel three-pronged approach to kill cancer cells selectively concomitant viral, double suicide gene, and radiotherapy, Hum. Gene Ther. 9 1323 (1998). 

The DNA-damaging agent bleomycin arrests the cell cycle of Jurkat cells defective in the G1 checkpoint in the G2 phase, and microtubule-affecting colchicine arrests it in the M phase [40]. Boromycin showed no effect on the cell cycle status of Jurkat cells at least up to 340 nM but potentiated anti-tumor activity of bleomycin in SCID mice inoculated with Jurkat cells. These data suggest that boromycin disrupts the cell cycle at the G2 checkpoint of cancer cells selectively, leading to sensitization of cancer cells to anti-cancer reagents. 

FIGURE 14.28 Transductional tai eting in virotherapy. Viruses, such as adenovirus, are used to infect and destroy cancer cells selectively. Spikes on the adenovirus are mutated so that they recognize unique receptors on cancer cells. The virus selectively infects and lyses the cancer cells. ( 2003 Terese Winslow.)... 

Gouaze V, Yu JY, Bleicher RJ, Han TY, Liu YY, Wang H, Michael M, Gottesman MM, Bitterman A, Giuliano AE, Cabot MC. Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther 2004 3 633-639. 

Cancer Cell Selection through Cell Death... 

Attempts are being made to find agents that will rupture the membranes of cancer cells selectively. For example amines, stich as 4-dodecylpyridine 14.20), with a pX a value between 5 and 9, are selectively accumulated by lysosomes because these have an acidic sap, as have cancer cells (p. 151). The amines enter the cells freely, being non-ionized and lipophilic, but are trapped as cations by the acidic sap and cannot escape. Because the cations (but not the neutral species) are detergents, the lysosomal membranes become ruptured, and it is hoped to adapt this phenomenon to anti-cancer therapy. 4-Dodecylpyridine is non-toxic to mice after intraperitoneal injection of 0.5 g/kg (Firestone, Pisano and Bonney, 1979). 

In 2002, British scientists developed a recombinant protein that was able to break down linamarin (Fig. 3.2) to hydrogen cyanide in cancer cells selectively (antibody-guided enzyme nitrile therapy, AGENT). However, the protein has major disadvantages and is unlikely to be useful as a medicine. 

Low molecular weight protamine (LWMP) is a powerful cellular uptake enhancer but its lack of specificity limits its use for cancer cell selective internalization of nanocarriers [122]. This was recently addressed by Gu et al. with paclitaxel-loaded... 

For further control of cancer cell selectivity, Zhu and coworkers developed tumor-hypoxia activated phototrigger systems using coumarin as the photosensitizer and nitro-imidazole as the hypoxia-sensitive imit [143]. Hypoxia-induced nitroimidazole reduction was required before photocleavage of coumarin and etoposide release for anticancer therapy. They showed cancer cell killing in vitro in aerobic conditions after illumination but not in a normal atmosphere. In aerobic tissues, nitroimidazole acts as an electron acceptor, preventing photocleavage and imspedfic drug release in normal tissues. 

M. Mitsunaga, M. Ogawa, N. Kosaka, L.T. Rosenblum, P.L. Choyke, and H. Kobayashi, Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules, Nat Med, 17 (12), 1685-91,2011. 

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