Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.

Abstract

We have extended our studies on the relationship between cisplatin/carboplatin-induced DNA damage in readily accessible tissue(s) and clinical response to therapy. Such an approach may assist in the study of cancer drug resistance and in establishing parameters for assessing human populations for sensitivity to DNA damaging agents in the environment. Platinum-DNA adduct levels were measured by atomic absorbance spectrometry. DNA repair capacity was assessed in human T-lymphocytes by the ability to repair cisplatin lesions in cellular DNA or in transfected plasmid DNA. In a "blinded" study of 21 patients receiving combination cisplatin/carboplatin drug therapy, there was a direct relationship between DNA damage in leukocytes and disease response (summary two-sided p = 0.00011). The cohort of patients had 15 different tumor types, suggesting that blood tissue and tumor tissue of an individual may process platinum-DNA damage similarly regardless of the tissue of origin of the tumor. In leukocytes in vivo, persistence and accumulation were prominent features of the cisplatin-DNA adduct profile. Functional DNA repair capacity has been studied in eight human leukocyte cell lines in vitro (three, T-cells; three, B-cells; one, monocytic; one, promyelocytic), using a host cell reactivation assay with cisplatin-damaged pRSVcat. In the three T cell lines studied, host cell reactivation efficiency was directly related to the cells' abilities to repair cisplatin-damaged cellular DNA (correlation coefficient = 0.993).(ABSTRACT TRUNCATED AT 250 WORDS)

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

“…This parameter was used by Schellens et al (1996) and Veal et al (2001) after cisplatin administration. Other authors used the adduct values measured at a certain time (Dabholkar et al, 1992;Gupta-Burt et al, 1993;Boffetta et al, 1998), the maximum of all values measured in several cycles (Reed et al, 1988) or the measurability of adducts (Reed et al, 1986;Poirier et al, 1987). The interindividual variability of adduct levels after administration of oxaliplatin was large, especially in comparison to the pharmacokinetic parameters.…”

Assessment of chemotherapy‐induced DNA damage in peripheral blood leukocytes of cancer patients using the alkaline comet assay

“…It interacts with topoisomerase II to form DNA-cleavable complexes and leads to the formation of active oxygen species that then cause predominantly single-strand breakage [44]. The platinum-containing drug cisplatin, on the other hand, is an efficient producer of interstrand; intrastrand and monofunctional adduct cross-linking in DNA [45]. As a consequence of simultaneous exposure in the course of chemotherapy in peripheral blood leukocytes of treated cancer patient a lot of single strand breaks, DNA fragments, and alkali-labile sites, which are predominantly measured in the alkaline comet assay, were provoked.…”

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

“…12,13 To determine the type of DNA damage induced by SK228, Hoechst 33342 dye displacement assay was first performed to investigate whether SK228 could bind to the minor groove of DNA to cause DNA damage. As shown in Figure 1c (left panel), DNA-interacting drug doxorubicin bound strongly to DNA minor groove to displace Hoechst 33342 dye, so the fluorescent of Hoechst dye was decreased.…”