Chemotherapy Side-Effects: Not All DNA Damage Is Equal

Boogaard, Winnie M. van den van den C.; Komninos, Daphne S. J.; Vermeij, Wilbert P.

doi:10.3390/cancers14030627

Cited by 186 publications

(79 citation statements)

References 162 publications

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“…Because both drugs are administered simultaneously, we can directly compare the impact of platinum and 5-FU mutagenesis in vivo in the same ASCs (i.e., genetically uniform with equal proliferation dynamics) as these drugs leave distinct mutational footprints 5,6 . We studied mutations in ASCs derived from the slowly renewing liver (cultured as intrahepatic cholangiocyte organoids 18 ) and the actively proliferating colon because these tissues show distinct mutational signatures upon aging, which suggests differences in the balance between DNA damage and repair that may affect treatment-induced mutagenesis as well 16,19 . Overall, our results indicate a differential permissiveness of ASCs in different tissues to acquire therapy-induced mutations for different chemotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Kuijk

Kranenburg

Cuppen

et al. 2022

Preprint

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Comprehensive analyses of genome-wide mutation profiles has revealed that specific anti-cancer drugs, such as 5-fluorouracil (5-FU), are highly mutagenic to cancer cells and cultured cells. The systemic administration of these chemotherapies presents a potential genotoxic hazard to healthy tissues, however, the true mutational impact on normal cells of patients is not known. Here, we examined genome-wide somatic mutation patterns in healthy adult stem cells (ASCs) of the colon or the liver from 14 colorectal cancer patients that received first-line systemic chemotherapy and/or local radiotherapy. The platinum-based chemo-drug Oxaliplatin induced 500-1000 mutations in each colon ASC of all treated patients. The effects of 5-FU treatment were more variable between cells and patients, ranging from a complete absence of 5-FU mutagenesis to the accumulation of up to 500 mutations in individual colon ASCs. In contrast with the colon, normal ASCs from the liver escaped platinum and 5-FU mutagenesis after systemic treatment. Local radiation therapy resulted in the accumulation of 50-100 deletions between 5bp to 10kbp and structural rearrangements in colon ASCs. Thus, while 5-FU and platinum drugs are highly effective at killing cancer cells, their systemic use does also lead to a concomitant increase of the mutational burden in long-lived normal stem cells responsible for tissue renewal and thus pose a potential source for developing second cancers.

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Section: Introductionmentioning

confidence: 99%

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Kuijk

Kranenburg

Cuppen

et al. 2022

Preprint

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“…[ 3,4 ] However, the low specificity, drug resistance, and the severe side effects seriously limit its therapeutic efficacy. [ 5,6 ] Benefiting from the repeatability, minimal invasiveness and short recovery time, photothermal therapy (PTT) has emerged as a new supplementary modality to the traditional chemotherapy of tumors. [ 7 ]…”

Section: Introductionmentioning

confidence: 99%

“…

However, the low specificity, drug resistance, and the severe side effects seriously limit its therapeutic efficacy. [5,6] Benefiting from the repeatability, minimal invasiveness and short recovery time, photothermal therapy (PTT) has emerged as a new supplementary modality to the traditional chemotherapy of tumors. [7] Gold nanoparticles (AuNPs) have been widely used as both carriers of chemotherapeutic agents and photothermal materials in the therapy of tumors, due to their excellent biocompatibility and strong near-infrared (NIR) absorption.

…”

mentioning

confidence: 99%

Spermine‐Responsive Intracellular Self‐Aggregation of Gold Nanocages for Enhanced Chemotherapy and Photothermal Therapy of Breast Cancer

Xie

Zhao

Shui

et al. 2022

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Improving the precise accumulation and retention of nanomedicines in tumor cells is one of the keys to effective therapy of tumors. Herein, supramolecular peptides capped Au nanocages (AuNCs) that may self‐aggregate into micron‐sized clusters intracellularly in response to spermine (SPM), leading to specific accumulation and retention of AuNCs in SPM‐overexpressed tumor cells, are developed. In this design, polydopamine (PDA) is in situ coated on the surface of AuNCs with doxorubicin (DOX) encapsulated. A small peptide, Phe‐Phe‐Val‐Leu‐Lys (FFVLK), is conjugated with PDA via esterification, and cucurbit[7]uril (CB[7]) is threaded onto the N‐terminal Phe via host‐guest interactions. Once the supramolecular peptide (CB[7]‐FFVLK) capped AuNCs are internalized in SPM‐overexpressed breast cancer cells, CB[7] can be competitively removed from FFVLK by SPM, due to the much higher binding affinity between CB[7] and SPM than that between CB[7] and Phe, leading to exposure of free FFVLK, which can subsequently self‐assemble and induce the aggregation of AuNCs to micron‐sized clusters, resulting in the significantly enhanced accumulation and retention of DOX‐loaded AuNCs in tumor cells. Under NIR laser irradiation, the enhanced photothermal conversion of AuNCs aggregates, together with photothermia‐induced release of DOX leads to synergistic photothermal therapy and chemotherapy against breast cancer.

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“…Cancer incidence and mortality continue to increase rapidly worldwide [ 4 , 5 ]. The conventional cancer chemotherapeutic drugs confer relevant toxic side effects [ 6 , 7 , 8 ], while their clinical efficacy is often obtained for limited periods of time, because drug resistance emerges and the tumors evolve [ 9 , 10 ]. Therefore, the development and discovery of novel therapeutic strategies are urgently needed to offer more effective and safe therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

et al. 2022

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Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by conventional drugs, such as the small molecules. Moreover, the mRNA itself retains oncological functions, and its targeting offers the double advantage of blocking the tumorigenic activities of the mRNA and the translation into protein. Finally, a large family of non-coding RNAs (ncRNAs) has recently emerged that are also dysregulated in cancer, but they could not be targeted by drugs directed against the proteins. In this context, this review describes how the oligonucleotide therapeutics targeting RNA or DNA sequences, are emerging as a new class of drugs, able to tackle the limitations described above. Numerous clinical trials are evaluating oligonucleotides for tumor treatment, and in the next few years some of them are expected to reach the market. We describe the oligonucleotide therapeutics targeting undruggable proteins (focusing on the most relevant, such as those originating from the MYC and RAS gene families), and for ncRNAs, in particular on those that are under clinical trial evaluation in oncology. We highlight the challenges and solutions for the clinical success of oligonucleotide therapeutics, with particular emphasis on the peculiar challenges that render it arduous to treat tumors, such as heterogeneity and the high mutation rate. In the review are presented these and other advantages offered by the oligonucleotide as an emerging class of biotherapeutics for a new era of precision anti-cancer medicine.

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Chemotherapy Side-Effects: Not All DNA Damage Is Equal

Cited by 186 publications

References 162 publications

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Spermine‐Responsive Intracellular Self‐Aggregation of Gold Nanocages for Enhanced Chemotherapy and Photothermal Therapy of Breast Cancer

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

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