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.

Keywords: chemo-radiotherapy (CRT); cis-diamminedichloroplatinum (cisplatin: CDDP); concurrent; radio-sensitizing; radiotherapy (RT); synergistic effect.

Figure 1

Major reaction. The major reaction occurs mainly in the cytoplasm. Radiation and CDDP give cells an identical excessive oxidative loading response, resulting in a synergistic effect leading to cell death. The metabolic response to the excessive oxidative loading by CDDP reaches its maximum within 6 h and is rapidly resolved thereafter. Therefore, it is necessary to administer CDDP within 6 h before or after radiation in order to obtain the synergistic effect. (A) Radical scavengers and NADH/NAD+ rate decrease → redox homeostasis perturbation → metabolic (Warburg effect, DNA repair, etc.) malfunctions. (B) Mitochondrial dysfunctions → more excessive and persistent oxidative stress, and apoptosis. (C) Oxidation of cell constituents (especially lipid peroxidation) → cell dysfunctions, destruction of cell components (DNA, etc.), ferroptosis.

Figure 2

Mechanism underlying the synergistic effect produced by overlapping of the same reaction. Chains lose their flexibility exponentially each time their joints are fixed. The same can be said for the cascade of normal metabolic reactions, which are intracellular chain reactions. It is well-known that cells can maintain homeostasis even if they sustain some damage, but homeostasis suddenly collapses when a certain amount of damage is accumulated. The schema in this figure illustrates that ① unfixed chains are very flexible and can take many forms; ② the chain retains some flexibility even if the joint is fixed in several places; and ③ as the number of fixed joints increases, the forms that the chain can take decrease exponentially and are extremely limited.

Figure 3

Minor reactions. The minor reactions take place in the nucleus. The complementary combination of radiation-induced primary DNA strand breaks and CDDP-induced DNA damages (DNA crosslink, etc.) synergistically results in DNA damage and then cell death. Since the crosslinks of DNA by CDDP are metabolized in a few hours, it may be necessary to perform RT within a few hours after the administration of CDDP in order to obtain a sufficient synergistic effect. Abbreviations: SSBs, single-strand breaks; DBSs, double-strand breaks.

Figure 4

The protocol regimens of each arm of three clinical trials of RT plus CDDP for head and neck cancer. (A) Do 2 Gy per 1 fr, 5 times a week. Continue this for 7 weeks. (B) Administer CDDP every 3 weeks (day 1, day 22, day 43) within a few hours before or after RT. The CDDP administration is 100 mg/m² per dose. (C) Initially, administer 5-FU for 5 consecutive days + simultaneous CDDP every 3 weeks (the addition of 5-FU increases the intensity of chemotherapy). Perform RT sequentially. The CDDP dose is 100 mg/m² per dose, the 5-FU dose is 1000 mg/m² per dose. (D) Administer a small quantity of CDDP once a week within a few hours before or after RT. The CDDP dose is 30 mg/m² per dose. Abbreviations: RT, radiotherapy; fr, fraction; CCRT, concurrent chemo-radiotherapy; SCRT, sequential chemo-radiotherapy; Gy, gray; mg, milligram; m², square meter.