Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies

Abstract

Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. “Overlap” refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. “Complementation” refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.

The dogma of Cetuximab and Radiotherapy in head and neck cancer – A dawn to dusk journey

“…Cisplatin and radiation interaction has been studied since 1970 s. The very concept of combining chemotherapy concurrent with radiation is that, even if they are less effective on their own, the combination renders them more effective owing to synergistic effects. Various mechanisms of interaction have been hypothesized and proven in preclinical studies as well [21] . Cisplatin being highly electron affinic, the platinum moiety enhances the free radical mediated damage induced by radiation by increasing the free radical generated by radiation and capturing the electrons released from irradiated DNA [43] .…”

“…Concurrent addition of cisplatin to RT uses the 3rd principle - chemotherapy enhancing the tumour response of RT as they interact at the molecular, cellular or patho-physiologic level resulting in an augmented anti-tumour effect. This effect is beyond the mere additive effect of each of the modalities leading to supra-additive or synergistic effect [21] . Enhancing tumour response by counteracting determinants associated with radio-resistance like EGFR over-expression is also a major rationale which is used in BRT, which probably fits into spatial cooperation.…”

Influence of alectinib and crizotinib on ionizing radiation - in vitro analysis of ALK/ROS1-wildtype lung tissue cells

“…Such unwanted effects may not be suggested for alectinib because of its already published high binding specificity [9] . Furthermore, the current standard of care in lung cancer is a combination of RT with chemotherapy harboring a risk of side effects in up to 20 % of all patients, based on strong synergistic interactions of IR + CT [ 9 , 35 ]. Regarding the clinical safety of concomitant IR with ALK-inhibitors, this combination lacks such synergistic interactions.…”

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity

“…Since then, more and more attention has shifted to the adverse drug reactions caused by cisplatin chemotherapy. Despite its efficacy in treating solid-state cancers ranging from the head-and-neck [9,10], to ovarian [11,12], and testicular [13,14], and several others [15,16], especially childhood-related cancers [17][18][19][20][21][22][23], the toxicity of cisplatin has put serious limitations on its clinical use as well as the long-term health outcomes and quality of life of cancer survivors. The adverse drug reactions caused by cisplatin and its toxicity profile have led to the development of several cisplatin-induced toxicities (CITs) [24][25][26], which appear to target specific parts of the body such as the kidneys, liver, neurons, and inner ear.…”