Centrosomal Amplification and Related Abnormalities Induced by Nucleoside Analogs - The Centrosome - page 267

16.1 Background
The centrosome is an organelle that regulates migration of chromosomes to the
daughter cells, and is also a microtubule organizer. Based on the multiple proteins
residing in the centrosome-associated protein matrix, centrosomes have been
implicated in other cellular functions including cell cycle transitions, such as G 1 to
S-phase, G 2 to mitosis, and metaphase to anaphase (D'Assoro et al. 2002 ; Doxsey
et al. 2005 ). Cells normally have one centrosome, which duplicates synchronically
with the phases of the cell cycle to generate two new centrosomes, each of which
comprises a pair of orthogonally placed centrioles. Most human carcinomas have
an abnormal centrosomal number that contributes to the genomic instability
characteristic of transformed cells (Carroll et al. 1999 ; Lingle et al. 1998 ; Pihan
et al. 1998 ; Satoh and Lindahl 1994 ). Additionally, it has been reported that
malfunction of the centrosome induces delay in the G 1 -S boundary of the cell cycle
(Hinchcliffe et al. 2001 ; Mikule et al. 2007 ). Some clastogenic agents may also
behave as aneugens, generating an array of both structural and numerical chro-
mosomal aberrations as well as chromosomal instability (Lengauer et al. 1997 ).
Zidovudine (3 0 -azido-3 0 -deoxythymidine, AZT), the first nucleoside reverse
transcriptase inhibitor (NRTI) used for HIV-1 therapy has been shown to induce
micronuclei, chromosomal aberrations, mutations, and telomeric attrition in vitro
and in vivo (IARC 2000 ; Olivero 2007 ). Additionally, AZT becomes incorporated
into eukaryotic DNA (Diwan et al. 1999 ; Olivero et al. 1997 ) and induces cell
cycle arrest with accumulation of cells in S-phase (Chandrasekaran et al. 1995 ;
Escobar et al. 2007 ; Olivero et al. 2005 , 2008 ; Viora et al. 1997 ).
16.2 Genotoxicity of Nucleoside Analogs
Nucleoside reverse transcriptase inhibitors (NRTIs) constitute a high widespread
type of drugs used in the therapy of AIDS. Used in monotherapy or in combination
with other drugs, their mechanism of action is based upon the ability to act as
chain terminators and the inhibition of the nucleotide binding site of the HIV-1
reverse transcriptase (Furman et al. 1986 ; Huang et al. 1990 ; St.Clair et al. 1987 ).
Usually administered as prodrugs, NRTIs become active through a cascade of
cytosolic phosphorylations. Activation of Zidovudine (ZDV), the first NRTI
approved by the US Food and Drug Administration, to the triphosphate form is
mediated by thymidine kinase, thymidylate kinase, and pyrimidine nucleoside
diphosphate kinase (St. Clair et al. 1987 ). Zidovudine acts as a HIV-1 reverse
transcriptase inhibitor able to reduce morbidity and mortality related with HIV-1
infection (Fischl et al. 1987 ); however, its use has been limited due to induced
toxicities (Richman et al. 1987 ). Although highly specific for HIV-1 reverse
transcriptase, NRTIs exhibit some affinity for cellular polymerases (Lim and
Copeland 2001 ); Parker et al. 1991 ). In a comprehensive review, Lee et al. report