An Ultraviolet Resonance Raman Spectroscopic Study of Cisplatin and Transplatin Interactions with Genomic DNA

Abstract

Ultraviolet resonance Raman (UVRR) spectroscopy is a label-free method to define biomacromolecular interactions with anticancer compounds. Using UVRR, we describe the binding interactions of two Pt(II) compounds, cisplatin (cis-diamminedichloroplatinum(II)) and its isomer, transplatin, with nucleotides and genomic DNA. Cisplatin binds to DNA and other cellular components and triggers apoptosis, whereas transplatin is clinically ineffective. Here, a 244 nm UVRR study shows that purine UVRR bands are altered in frequency and intensity when mononucleotides are treated with cisplatin. This result is consistent with previous suggestions that purine N7 provides the cisplatin-binding site. The addition of cisplatin to DNA also causes changes in the UVRR spectrum, consistent with binding of platinum to purine N7 and disruption of hydrogen-bonding interactions between base pairs. Equally important is that transplatin treatment of DNA generates similar UVRR spectral changes, when compared to cisplatin-treated samples. Kinetic analysis, performed by monitoring decreases of the 1492 cm band, reveals biphasic kinetics and is consistent with a two-step binding mechanism for both platinum compounds. For cisplatin-DNA, the rate constants (6.8 × 10 and 6.5 × 10 s) are assigned to the formation of monofunctional adducts and to bifunctional, intrastrand cross-linking, respectively. In transplatin-DNA, there is a 3.4-fold decrease in the rate constant of the slow phase, compared with the cisplatin samples. This change is attributed to generation of interstrand, rather than intrastrand, adducts. This longer reaction time may result in increased competition in the cellular environment and account, at least in part, for the lower pharmacological efficacy of transplatin.

UV Resonance Raman Study of Apoptosis, Platinum‐Based Drugs, and Human Cell Lines

“…Interestingly, the cisplatin stereoisomer, transplatin (TP), is clinically ineffective. An explanation of the inactivity is based on the type of DNA adducts formed by this isomer as well as its increased chemical reactivity. This reactivity makes TP susceptible to rapid deactivation in cells …”

“…These advantages offer an opportunity to study intact cells without the addition of markers, dyes, or contrast-enhancing agents. [11,12] Importantly, when used to characterize intact cells, UVRR spectroscopy offers a significant improvement in spectral specificity over other Raman techniques, due to the fact that the most abundant biomolecules in cells, including proteins, nucleic acids, and unsaturated lipids, have optical absorption in the UV region. Under resonance Raman conditions, where the incident excitation energy overlaps with an electronic transition of the target molecule, the Raman intensity of the target molecule is enhanced by as much as 10 6 compared to non-resonance Raman scattering.…”

Syntheses, Characterization, and Preliminary Evaluation of Potential Ruthenium Anticancer Complexes Containing Schiff Base Ligands

“…Since the discovery of the bioactivity of cis-diamminedichloroplatinum(II), commonly known as cisplatin in 1965 by Dr. Rosenberg et al 4,5 and its subsequent approval by the U.S Food and Drugs Administration (FDA) in 1978, 6 metallochemotherapeutics, especially platinumbased compounds have been successfully used for treatment of many neoplastic conditions.…”

“…5 The use of cisplatin as a chemotherapeutic agent greatly improved the survival chances for many cancer patients. For example, the drug increased the rate of cure of testicular cancer from less than 10% to 90% in modern oncotherapy 6 and almost 100% when the cancer cells are in stage 1 of development 5 where the cancer has attacked tissues next to the testicle, but not lymph nodes, or more distant cells in the body. In North America and Europe, it is estimated that more than one million cancer patients are on cisplatin treatments.…”

“…In North America and Europe, it is estimated that more than one million cancer patients are on cisplatin treatments. 6 Cisplatin treats cancer cells mainly by cross-linking deoxyribonucleic acid (DNA) and…”