Platinum Drug-DNA Interactions in Human Tissues Measured by Cisplatin-DNA Enzyme-Linked Immunosorbent Assay and Atomic Absorbance Spectroscopy

Abstract

Studies of platinum drug-DNA adduct formation in tissues of cancer patients have involved both atomic absorbance spectroscopy (AAS), which measures total DNA-bound platinum, and anti-cisplatin-DNA enzyme-linked immunosorbent assay (ELUSA), which detects a fraction of the AAS-measurable adduct. These studies were designed to explore mechanisms ofdrug-DNA interactions, to make correlations with clinical outcome, and possibly to validate DNA adduct measurements for use in occupational and environmental bioHmoitoring. The resls, determined by both ELISA and AAS, demonstrate that cisplatin and its analog carboplatin bind to DNA in many human organs, including kidney, brain, peripheral nerve, and bone marrow, which are sites for drug ticity. Platinum was also observed bound to ovarian tumor DNA. The adducts were highly persistent, being measurable in tissues obtained at autopsy upto 15 months after the last administration of platinum chemotherapy. A comparison ofbood cell DNA adduct levels, determined by ELISA, and the clinical response of 139 patients with ovarian, testicular, colon, or breast cancer demonstrated a strong correlation between failure to form DNA adducts and failure of therapy. Conversely, patients who formed high levels of DNA adduct were most likely to respond favorably. A similar correlation was not observed for adducts determined by AAS; that is, the average total DNA-bound platinum levels were the same for patients who did not respond to therapy and for patients who had any kind of response. Thus, in this study, human blood cell DNA adducts measured by ELISA correlate with tumor remission, while those measured by AAS do not.

A Gynecologic Oncology Group Study of Platinum-DNA Adducts and Excision Repair Cross-Complementation Group 1 Expression in Optimal, Stage III Epithelial Ovarian Cancer Treated with Platinum-Taxane Chemotherapy

“…A larger study is therefore needed to definitively evaluate whether or not a relationship exists between platinum-DNA adduct levels and disease status following primary treatment with paclitaxel plus cisplatin or carboplatin in women with optimally debulked stage III EOC. Previous studies in a variety of cancers including ovarian cancer have shown a positive relationship between platinum-DNA adducts and disease response (8)(9)(10)(11)(12)(13)(14), no association between platinum-DNA adducts and disease response (12,17,18), or an Abbreviation: AU, arbitrary units. *Cox regression analysis for modeling the relative risk of disease progression.…”

“…Previous studies evaluated the relationship between platinum-DNA adducts in peripheral leukocytes and disease response but not PFS or OS in a variety of cancers including ovarian cancer (8)(9)(10)(11)(12)(13)(14)(16)(17)(18) or between platinum-DNA adducts in either buccal cells or tumor and disease response in a variety of cancers (19), OS in NSCLC (20), or with PFS and OS in HNSCC (21). In these studies, platinum-DNA adducts were assessed using an ELISA (8)(9)(10)(11)(12)14) atomic absorbance spectroscopy (12-14, 16, 17), inductively coupled plasma-mass spectroscopy (18), immunocytochemistry (19,20), or 32 P postlabeling (21). This study showed that the presence of platinum-DNA adducts in PBL 20 to 28 h after the first cycle of chemotherapy was associated with better OS, but not with PFS or the results of SLL.…”

“…The level of platinum-DNA adducts in PBL has been shown either to be positively correlated with disease response in a number of cancers, including testicular, breast, colon, lung, esophageal, and ovarian cancer (8)(9)(10)(11)(12)(13)(14), or with the degree of myelosuppression in children with cancer receiving cisplatin therapy (15), to be negatively correlated with disease response in advanced germ cell cancer (16) or to not be associated with disease response in patients with testicular, ovarian, or breast cancer (12,17,18). Furthermore, a positive association has not only been shown between platinum-DNA adducts in buccal cells and disease response in a variety of cancers, including testicular, breast, ovarian, and colon cancer (19), but also between platinum-DNA adducts in buccal cells and better OS in non-small cell lung cancer (NSCLC; ref.…”

Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo

“…In patients with the same type of tumour, a fairly large interindividual variation in DNA adduct levels, measured in white blood cells (WBCs), has been observed (Fichtinger-Schepman et al, 1990;Parker et al, 1993;Poirier et al, 1993;Reed et al, 1988Reed et al, , 1993Schellens et al, 1996). These clinical investigations provided evidence that higher adduct levels correlate with a better clinical outcome.…”

Electrochemical Methods for Probing DNA Damage Mechanisms and Designing Cisplatin-Based Combination Chemotherapy

“…Conventional methods include: gel electrophoresis [14], restriction enzyme assay [22,23], high-performance GC/MS [24] and ELISA [25]. In addition, fluorescent oligonucleotide molecular beacons were used for detection of single base polymorphism [26].…”