Purine analog resistance

The target cells used in purine analog resistance assays have almost all been fibroblast-like, such as the V79 and CHO lines, which have displayed little ability to activate carcinogens, other than polycyclic aromatic hydrocarbons (45). This deficiency has been overcome by providing... 

C. Tong and G. M. Williams, Induction of purine analog-resistant mutants in adult rat liver epithelial lines by metabolic activation-dependent and -independent carcinogens, Mutat. Res. 55,339-352 (1978). 

Dhainaut, A., Regnier, G., Tizot, A., Pierre, A., Leonce, S., Guilbaud, N., Kraus-Berthier, L. and Atassi, G. (1996) New purines and purine analogs as modulators of multidrug resistance. Journal of Medicinal Chemistry, 39, 4099-4108. 

An ADA-resistant purine analog, cladribine (2-chlorodeoxyadenosine 2-CdA) has demonstrated potent activity in hairy cell leukemia, CLL, and low-grade lymphomas. After intracellular phosphorylation by deoxycytidine kinase and conversion to cladribine triphosphate, it is incorporated into DNA. It produces DNA strand breaks and depletion of NAD and adenosine triphosphate (ATP), as well as apoptosis, and is a potent inhibitor of ribonucleotide reductase. The drug does not require cell division to be cytotoxic. Resistance is associated with loss of the activating enzyme, deoxycytidine kinase, or escape of ribonucleotide reductase from inhibition. 

G. M. Williams, C. Tong, and J. J. Berman, Characterization of analog resistance and purine metabolism of adult rat-liver epithelial cell 8-azaguanine-resistant mutants, Mutat. Res. 49, 103-115 (1978). 

The development of resistance of neoplasms to the purine analog, 8-azaguanine, has been correlated with the absence or inactivity of a specific enzyme system. Apparently, when the growth of a tumor was suppressed... 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

Cladribine (2-chlorodeoxyadenosine 2-CDA) is a purine nucleoside analog that is resistant to inactivation by adenosine deaminase. The triphosphate form of this agent is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination. Cladribine s antitumor activity is unusual for an antimetabolite in that it affects both actively dividing and resting cancer cells. Like fludarabine, cladribine possesses immunosuppressive effects that place patients at risk for serious opportunistic infections. ... 

Didanosine is a purine nucleoside analog active against HlV-1, HIV-2, and HTLV-1. After entering the cell, it is converted by phosphorylation to the active anaboUte dideoxyadenosine 5 -triphosphate. Single codon mutations, including TAMs, can contribute to didanosine resistance. 

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