Drug Sensitization

Miltefosine, an alkylphosphocholine derivative, is a new antileishmanial drug and the first effective oral treatment of visceral leishmaniasis. However, there are concerns regarding teratogenicity, rapid emergence of resistance, and variable cure rates, possibly due to species differences in drug sensitivity. The mechanism of action of miltefosine is not known. 

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

Ludmerer SW, Graham DJ, Boots E, Murray EM, Simcoe A, Markel EJ, Grobler JA, Flores OA, Olsen DB, Hazuda DJ, LaFemina RL (2005) Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob Agents Chemother 49 2059-2069... 

Viruses that contain amino acid substitutions in the sialidase that impart resistance to the developed inhibitors have been isolated from serial passage of virus in the presence of drug in cell culture and from the clinical setting (reviewed in McKimm-Breschkin 2000 Zambon and Hayden 2001 Cinatl et al. 2007a Reece 2007). In addition, influenza B virus variants with reduced drug sensitivity have been isolated from previously untreated patients (Hurt et al. 2006 Hatakeyama et al. 2007). The types of mutations that are observed are sub-type specific. The mutations present in variants isolated from clinical samples are shown in Table 1, and their locations within the sialidase active site are shown diagrammatically in Fig. 9. 

In reviewing intraarterial infusion of microencapsulated anticancer agents and its clinical applications, Nemoto (124) concluded that this mode of treatment can be used for a wide variety of tumors, providing remarkable therapeutic effects with minimal systemic toxicity. However, 25% of the treated tumors failed to respond, which was thought to be attributable to either inadequate catheterization, inadequate dose relative to tumor size, insufficient tumor vascularity, low drug sensitivity, or a combination of these factors. More carefully designed studies will be necessary before this technique is likely to meet with widespread acceptance. 

Barry C.E. Mdluli K. (1996) Drug sensitivity and environmental adaptation of mycobacterial cell wall components. Trends Microbiol, 4, 275-281. 

Chamber J et al. DNA microarrays of the complex human cytomegalovirus genome profiling kinetic class with drug sensitivity of viral gene expression. J Virol 1999 73 5757-5766... 

Schuhmann, D. et al., Adverse immune reactions to gold. I. Chronic treatment with an Au(I) drug sensitizes mouse T cells not to Au(I), but to Au(III) and induces autoantibody formation. J. Immunol., 145, 2132, 1990. 

Distribution of Primaquine-Sensitive Individuals in the Various Population Groups. Primaquine sensitivity was found in Negroes (B7, B19, C3, C7, G6, G7, G18, H21, M7), Caucasians (G18, L3, M7, W3), and certain Jewish tribes (S21, S23). The phenomenon could be detected in 4.6% of an unselected population of 305 North Americans. In healthy Negroes the sensitivity was more common (7.2%) than in Caucasians (1.3%) (G18). In the Jewish population, the defect was found in 20% of the non-Ashkenazic Jews originating from Iraq and Persia, in 5% from Yemen and Turkey, and in 2% from North Africa. Also 3% of the Arabs in Israel showed drug sensitivity. 

B8. Beutler, E., Congenital metabolic abnormalities of the erythrocyte Drug sensitivity and galactosemia. Proc. 4th Intern. Congr. Clin. Chem., Edinburgh, I960, pp. 110-119 (1961). 

BIO. Beutler, E., Robson, M., and Buttenwieser, E., The mechanism of glutathione destruction and protection in drug sensitive and nonsensitive erythrocytes. In vitro studies. J. Clin. Invest. 38, 617-628 (1957). 

G6. Gilles, H. M., and Ikeme, A. C., Hemoglobinuria among adult Nigerians due to glucose-6-phosphate dehydrogenase deficiency with drug sensitivity. Lancet i, 889-891 (1960). 

K. D. Pleiotropic effects of Ubp6 loss on drug sensitivities and yeast prion are due to depletion of the free ubiquitin pool, J Biol Chem, 2003, 278, 52102-15. 

Cabot, M. C., Giulano, A. E., Han, T-Y., and Liu, Y-Y., 1999, SDZ PSC 833, the cyclosporin A analog and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drag-resistant cancer cells. Cancer Res. 59 880-885. 

---