Mechanisms of Interaction with Conventional Chemotherapy

The concomitant use of conventional chemotherapy agents such as the fluoropyrimidines and the platinum analogues during radiation therapy is the standard of care for neoadju-vant, postoperative adjuvant and definitive therapy in the treatment of locally advanced cancers of the head and neck, lung, and throughout the gastrointestinal tract, including esophageal, gastric, pancreas, rectal, and anal cancers. The results of various Phase 3 clinical trials of concomitant combined modality therapy using these drugs are reviewed throughout this textbook under the disease-specific sites. Indeed, the success of these concomitant combined modality treatments for the locally advanced cancers is probably the most significant advances in cancer therapy during the past 10 to 15 years.65-67 Surprisingly, in spite of such success, the cellular and molecular mechanisms of interaction resulting in tumor radiosensitization remain poorly understood. Although an in-depth review of our current understanding of the greater than additive interactions of conventional chemotherapy drugs is beyond the scope of the chapter, the reader is referred to three recent reviews.65-67 A brief overview of these drug-radiation interactions is summarized as follows.

5-Fluorouracil (5-FU) is clearly the most commonly used drug as a radiosensitizer, with the principal mechanism of sensitization related to inhibition of thymidylate synthase (TS) with subsequent progression through the G1 checkpoint (restriction point) into S phase with altered (perturbed) triphosphate pools and reduced DNA repair.68 As such, tumors with high levels (overexpression) of TS, which are known to be clinically resistant to 5-FU cytotoxicity, are probably also resistant to 5-FU-based radiosensitization. Two other enzymes involved in nucleoside metabolism including dihydropyrimidine dehydrogenase (DPD), a 5-FU catabolic enzyme, and thymidine phosphorylase (TP) may also be key regulators of fluoropyrimidine radiosensitization, including the use of oral prodrugs such as UFT and capecitabine.66

Chemotherapy drugs that target ribonucleotide reductase (RR), the rate-limiting enzyme in deoxynucleotide metabolism, can also result in clinical radiosensitization.66,67 These drugs include hydroxyurea (HU) and gemcitabine (dFdCyd). It is known that ionizing radiation can cause a posttranscriptional overexpression of RR69 and that the mechanism of radiosensitization appears to be progression into S phase under altered triphosphate pools (particularly dATP).70

The platinum analogues, including cisplatin, carboplatin, and oxaliplatin, are also commonly used as clinical radiosen-sitizers in head and neck cancers, non-small cell lung cancers, bladder cancers, and locally advanced cervical cancers. Several potential mechanisms of drug-radiation interactions with the platinum analogues have been proposed, including enhanced formation of toxic platinum-DNA adducts and crosslinks in the presence of IR free radicals; cell-cycle arrest at G2/M with reduced DNA repair; and enhanced cellular platinum uptake by IR.68

Although the enhanced local control and improved survival rates have convinced the oncology community to consider these concomitant combined modality approaches as the current standard of care for many locally advanced solid tumors, there is also an enhancement in both acute (e.g., mucositis, myelosuppression) and late (e.g., esophageal, bowel strictures) normal tissue toxicities. Thus, more carefully designed clinical trials are still needed to measure the therapeutic gain and to test in patients the proposed mechanisms of these drug-radiation interactions leading to radiosensitization using noninvasive imaging techniques including PET and MR spectroscopy. Even in this era of mo-lecularly targeted therapy, the oncology community should not overlook the success of these drug-radiation interactions and should continue to study the molecular targets of these leading to radiosensitization.

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