Platinum-based Anticancer Agents Research Articles

In defense of platinum: Amino acidic polydentate ligands as a shield against sulphur-donor nucleophilic attacks

The interactions of sulfur-containing peptides and proteins with platinum-based anticancer agents are of significant interest in the field of bioinorganic chemistry. We previously modified the lead compound potassium {trichlorido[η2-(but-3-en-1-yl)-2-acetoxybenzoate]platinate(II)} (Pt-butene-ASA) by exchanging two chlorido ligands for an amino acid chelating ligand to improve its stability in aqueous solutions. In the current study, we demonstrate how this amino acid ligand strengthens the inertness of this class of complexes against sulfur-containing compounds. We incubated four complexes, each bearing an amino acid chelating ligand, with various sulfur-containing compounds of biological interest, such as DMSO, methionine, glutathione, and substance P. The reactions were monitored using NMR spectroscopy and mass spectrometry, allowing the identification by combination with IR ion spectroscopy of exotic pentacoordinate platinum(II) complexes as reaction intermediates. The results indicated that the reactivity of complexes 1–4 ((ethene,N-trans)(l-alaninato-N,O)chlorido(η2-ethene)platinate(II), (ethene,O-trans)(β-alaninato-N,O)chlorido(η2-ethene)platinate(II), (l-histidinato-N,N)chlorido(η2-ethene)platinate(II), and (olefin,N-trans)(l-alaninato-N,O)chlorido(η2-(but-3-en-1-yl)-2-acetoxy benzoate)platinate(II), respectively) is determined by the inner coordination sphere, and the addition of an amino acid ligand significantly reduces the rate of nucleophilic substitutions by sulfur-containing nucleophiles. In particular, the N,ethylene-trans isomers reacted only to a low extent with the free thiol in glutathione, while the O,ethylene-trans isomer was completely consumed within 2 h. Complex 4, the new lead compound, showed low reactivity towards S-nucleophiles in general, which confirms the concept of using amino acids as biocompatible bidentate ligands to adjust the reactivity and stability of this kind of metallodrugs.

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 μM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

Cationic cyclometalated platinum (II) complexes of metformin with self-assembly and AIE behavior as nuclear and mitochondrial targeted anticancer theragnostic agents

Self-assembly and AIE (Aggregation-induced emission) of cyclometalated platinum (II) complexes have attracted lots of attention. The high hydrophilia and low permeability of metformin (Met) has greatly hindered its further clinical application, herein, our work rationally designed and synthesized a pair of theragnostic cyclometalated platinum (II) - metformin complexes. Pt1 and Pt2 can improve bioactivity of Met significantly, and AIE deep-red emission can be mediated by tuning chemical structure of auxiliary ligand in compounds. Moreover, self-assembly of two Pt (II) complexes was revealed, as well as mitochondria and nuclear targeting ability of Pt2 were newly obtained during an AIE process. Meanwhile, Pt2 exhibits 186- and 53-fold enhanced antiproliferative activity compared with Met and Met-free complex analogue, their anticancer mechanisms were also investigated. Herein, our work provides a novel strategy for designing multi-functional platinum-based anticancer theragnostic agents.

Imaging of Subcellular Distribution of Platinum in Single Cells Using Laser Ablation Inductively Coupled Plasma Mass Spectrometry.

Laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) is a well-established and sensitive analytical technique, which provides high-resolution imaging of endogenous elements, element tagged-markers, metal-containing nanoparticles, and metallodrugs within cells. Here we describe a protocol for imaging the subcellular distribution of platinum within A549 cells, following their incubation with the platinum-based anticancer agent, Oxaliplatin. We outline the essential steps in sample preparation and instrumental setup and discuss how the current generation of low-dispersion instruments facilitates new approaches to data acquisition and image processing. The protocol described herein can be easily adapted for other cell lines and metal-containing labeling agents.

Clinical response of pancreatic cancer bearing a germline BRCA2 p.I3169M fs*48 variant for platinum-based drug and PARP inhibitor.

Pancreatic cancer is a malignancy with a high mortality rate, accounting for 37 000 people annually in Japan. It is rarely diagnosed in a resectable state, and effective medicines for its advanced stage are scarce. Some pancreatic cancer is hereditary, and ~10% have germline mutations of Breast cancer 1/2 (BRCA1/2). BRCA1/2 are key molecules involved in homologous recombination to repair DNA double-strand break. Platinum-based drugs and poly Adenosine diphosphate ribose (ADP) ribose polymerase inhibitors that induce synthetic lethality would be theoretically effective in patients with loss-of-function mutations in BRCA1/2. Strictly speaking, some discrepancy between the pathogenicity of BRCA1/2 and their drug sensitivity might be expected. Hence, we report that platinum-based anticancer agents and poly ADP ribose polymerase inhibitors were effective against pancreatic cancer bearing BRCA2 p.I3169M fs*48.

H-Dot Mediated Nanotherapeutics Mitigate Systemic Toxicity of Platinum-Based Anticancer Drugs.

Platinum-based anticancer agents have revolutionized oncological treatments globally. However, their therapeutic efficacy is often accompanied by systemic toxicity. Carboplatin, recognized for its relatively lower toxicity profile than cisplatin, still presents off-target toxicities, including dose-dependent cardiotoxicity, neurotoxicity, and myelosuppression. In this study, we demonstrate a delivery strategy of carboplatin to mitigate its off-target toxicity by leveraging the potential of zwitterionic nanocarrier, H-dot. The designed carboplatin/H-dot complex (Car/H-dot) exhibits rapid drug release kinetics and notable accumulation in proximity to tumor sites, indicative of amplified tumor targeting precision. Intriguingly, the Car/H-dot shows remarkable efficacy in eliminating tumors across insulinoma animal models. Encouragingly, concerns linked to carboplatin-induced cardiotoxicity are effectively alleviated by adopting the Car/H-dot nanotherapeutic approach. This pioneering investigation not only underscores the viability of H-dot as an organic nanocarrier for platinum drugs but also emphasizes its pivotal role in ameliorating associated toxicities. Thus, this study heralds a promising advancement in refining the therapeutic landscape of platinum-based chemotherapy.

Synthesis, Characterization, DNA Synergy and Molecular Docking Studies of Novel 1,10-Phenanthroline Derived Mixed Ligand Metal(II) Complexes

The effect of tumour and all its related costs, both human and commercial factor is driving the exploration for novel curative medicines.Although platinum-based anticancer drugs have shown considerable success, their use is complicated by a number of drawbacks. Therefore, this study is mainly designed for transition metal complex based chemotherapeutic agents to reduce the obstacles for platinum-based anticancer agents presently used. Herein, novel mixed ligand-metal(II) complexes derived from 9-anthraldehyde, 2-aminophenol, metal chlorides and 1,10-phenanthroline (co-ligand) were synthesized and characterized using several spectral techniques, which revealed that they possess an octahedral structure. The interaction of calf thymus DNA (CT-DNA) with synthesized compounds confirmed that the compounds are binded with DNA via intercalation. The mode of interaction was affirmed by the docking simulations, where the synthesized compounds were docked with EGFR protein and 1B-DNA through intercalation. The biological screening results revealed that the synthesized complexes exhibited superior anti-pathogenic screening properties compared to ligands. The proliferation resistance against cancer cells and free radical scavenger studies of prepared compounds indicated that the presence of heterocyclic ligand is an important factor for boosting the anticancer potential and radical scavenger skill.

The Challenging Treatment of Cisplatin-Resistant Tumors: State of the Art and Future Perspectives.

One of the main problems in chemotherapy using platinum drugs as anticancer agents is the resistance phenomenon. Synthesizing and evaluating valid alternative compounds is challenging. This review focuses on the last two years of progress in the studies of platinum (II)- and platinum (IV)-based anticancer complexes. In particular, the research studies reported herein focus on the capability of some platinum-based anticancer agents to bypass resistance to chemotherapy, which is typical of well-known drugs such as cisplatin. Regarding platinum (II) complexes, this review deals with complexes in trans conformation; complexes containing bioactive ligands, as well as those that are differently charged, all experience a different reaction mechanism compared with cisplatin. Regarding platinum (IV) compounds, the focus was on complexes with biologically active ancillary ligands that exert a synergistic effect with platinum (II)-active complexes upon reduction, or those for which controllable activation can be realized thanks to intracellular stimuli.

Emerging role of non-coding RNAs in resistance to platinum-based anti-cancer agents in lung cancer.

Platinum-based drugs are the first line of therapeutics against many cancers, including lung cancer. Lung cancer is one of the leading causes of cancer-related death worldwide. Platinum-based agents target DNA and prevent replication, and transcription, leading to the inhibition of cell proliferation followed by cellular apoptosis. About twenty-three platinum-based drugs are under different stages of clinical trials, among cisplatin, carboplatin, and oxaliplatin are widely used for the treatment of various cancers. Among them, cisplatin is the most commonly used drug for cancer therapy, which binds with RNA, and hinders the cellular RNA process. However, long-term use of platinum-based drugs can cause different side effects and has been shown to develop chemoresistance, leading to poor clinical outcomes. Chemoresistance became an important challenge for cancer treatment. Platinum-based chemoresistance occurs due to the influence of intrinsic factors such as overexpression of multidrug resistance proteins, advancement of DNA repair mechanism, degradation, and deactivation of intracellular thiols. Recently, epigenetic modifications, especially non-coding RNAs (ncRNAs) mediated gene regulation, grasp the attention for reversing the sensitivity of platinum-based drugs due to their reversible nature without altering genome sequence. ncRNAs can also modulate the intrinsic and non-intrinsic mechanisms of resistance in lung cancer cells. Therefore, targeting ncRNAs could be an effective approach for developing novel therapeutics to overcome lung cancer chemoresistance. The current review article has discussed the role of ncRNA in chemoresistance and its underlying molecular mechanisms in human lung cancer.

Cisplatin-induced cell death increases the degradation of the MRE11-RAD50-NBS1 complex through the autophagy/lysosomal pathway

Cisplatin and other platinum-based anticancer agents are among the most widely used chemotherapy drugs in the treatment of different types of cancer. However, it is common to find patients who respond well to treatment at first but later relapse due to the appearance of resistance to cisplatin. Among the mechanisms responsible for this phenomenon is the increase in DNA damage repair. Here, we elucidate the effect of cisplatin on the MRN (MRE11-RAD50-NBS1) DNA damage sensor complex. We found that the tumor suppressor FBXW7 is a key factor in controlling the turnover of the MRN complex by inducing its degradation through lysosomes. Inhibition of lysosomal enzymes allowed the detection of the association of FBXW7-dependent ubiquitylated MRN with LC3 and the autophagy adaptor p62/SQSTM1 and the localization of MRN in lysosomes. Furthermore, cisplatin-induced cell death increased MRN degradation, suggesting that this complex is one of the targets that favor cell death. These findings open the possibility of using the induction of the degradation of the MRN complex after genotoxic damage as a potential therapeutic strategy to eliminate tumor cells.

Induction of immunogenic cell death by novel platinum-based anticancer agents

Traditional platinum-based anticancer drugs, led by cisplatin, play an important role in chemotherapy. However, the development of platinum compounds is limited due to serious toxicity and side effects. In recent years, studies have showed that immunogenic cell death (ICD) may be one of the potential action mechanisms of classical platinum drugs, such as oxaliplatin. This strategy combining chemotherapy and immunotherapy can effectively utilize the body's immune system to help platinum compounds to fight against tumors, and the dose can be appropriately reduced to limit toxic side effects. The induction of ICD by platinum compounds has become a research hotspot and one of the future development directions of metal drugs. Here, the progress of platinum compounds were collected and comprehensively summarized, their capacity of ICD induction and mechanism of action are exposed, providing reference for the design and synthesis of new anticancer platinum ICD inducers.

A novel therapy to combat non-small cell lung carcinoma (A549) using platinum (IV) and barium titanate conjugate

Lung cancer is the most commonly diagnosed and leading cause of carcinoma related death in the world. Platinum based chemotherapy through cisplatin is one of the most common drug of choice to the control of disease progression and survival of the non small cell lung carcinoma patients. But cases of drug resistance and harmful side effects of cisplatin treatment motivated us to develop a platinum-based nanoformulation with improved bio-distribution and minimum toxicity. A cisplatin prodrug [Pt(IV) prodrug] was conjugated to functionalized hydrothermally synthesized barium titanate nanoparticles (BTNPs) through coupling reaction to form a novel barium titanate and platinum(IV) prodrug conjugate i.e., BT-Pt(IV) conjugate. In the present study, BTNPs, Pt(IV) prodrug, and BT-Pt(IV)conjugate were characterized by elemental analysis. In vitro assay of cellular uptake and cytotoxicity against non-small cell lung carcinoma (A549) cell line and noncancerous HEK293 cells were evaluated. BT-Pt(IV) conjugate demonstrated greater and sustained antiproliferative activity in a dose and time-dependent manner compared to cisplatin in A549 cells. The IC50 value of BT-Pt (IV) conjugate was estimated to be 5.42 μg/mL which was significantly less (almost 50%) than cisplatin (12.04 μg/mL). The in vitro mechanistic studies revealed that the BT-Pt(IV) conjugate increased the intracellular basal reactive oxygen species levels, which have led to the death of non-small cell lung carcinoma. However, HEK293 cells could escape the anti-proliferative capacity of the new drug conjugate. BaTiO3 has been chosen for its effectiveness as a biocompatible uptake enhancer of drugs. The current study has explored the therapeutic efficacy of a novel nanoformulation based on a clinically approved platinum-based anti-cancer agent with less toxicity and more bioavailability.

Assessment of antitumor activity of BP-C1, a platinum-based anticancer agent with a lignin-derived polymeric ligand, in autochthonous induced and spontaneous carcinogenesis rodent models

BackgroundA standard approach to study the anticancer activity of novel drugs is their testing in animals with inoculated tumors, which has some limitations. An alternative is the use of spontaneous or carcinogen-induced tumor models as they have better translation potential. The carcinogen-induced and transgenic tumor models were used to assess the antitumor activity of BP-C1, a platinum-containing drug with lignin-derived polymeric ligand. MethodsWe used female Swiss-H-derived mice and Wistar female rats to induce autochthonous tumors via exposure to benzo[a]pyrene and 1,2-dimethylhydrazine, respectively. Additionally, transgenic HER-2/neu FVB/N female mice, prone to the development of spontaneous mammary carcinomas, were used. ResultsAntitumor activity of BP-C1 was observed in soft tissue sarcomas, induced by benzo[a]pyrene. The animals treated with BP-C1 exhibited more stabilizations and therapy responses compared to placebo controls. The efficacy of BP-C1 was somewhat reduced compared to cyclophosphamide; however, their combination resulted in an enhanced antitumor effect. For the 1,2-dimethylhydrazine-induced rat colon cancer model, BP-C1 reduced tumor multiplicity by 21–41 %. For mammary adenocarcinomas in HER-2/neu FVB/N mice, short-termed complete responses were observed in the BP-C1 groups with a frequency of 12–13 %, while complete responses were absent in the placebo group. ConclusionThe results acquired indicated a wide spectrum of antitumor activity of BP-C1.

Oxidative stress imposed in vivo anticancer therapeutic efficacy of novel imidazole-based oxidovanadium (IV) complex in solid tumor

Vanadium is a transitional metal having several therapeutic aspects that can be exploited for its anticancer activity. Herein, we have verified anticancer effectivity of synthesized novel water soluble mononuclear dipicolinic acid-1-allyl imidazole-based oxidovanadium (IV) complex [VOL(1-allylimz)2] with respect to anticancer effectivity of known standard platinum-based anticancer agent cisplatin. In current work, we have verified VOL(1-allylimz)2 as highly potential anticancer agent selectively against human breast cancer cells. VOL(1-allylimz)2 has been noticed to elicit dose dependent cytotoxicity in MCF-7 cell line through induction of intracellular oxidative stress and mitochondrial membrane potential. Apart from in vitro validation, in vivo studies in male Swiss Albino mice also have seen to portray dose-dependent anticancer effect of [VOL(1-allylimz)2], where indications of oxidative stress induction became prominent too. Besides, both mitochondrial as well as extra-mitochondrial apoptosis in tumor cells have been shown to be induced by [VOL(1-allylimz)2] treatment, together enforcing its anticancer potency. In contrast to cisplatin, which shows high chances of nephrotoxicity in cancer patients, [VOL(1-allylimz)2] has been found to be comparatively safe for in vivo studies.

Advancements in the Use of Platinum Complexes as Anticancer Agents.

The platinum (II) complexes as anticancer agents have been well explored for the development of novel analogs. Yet, none of them achieved clinical importance in oncology. At present, anticancer compounds containing platinum (II) complexes have been employed in the treatment of colorectal, lung, and genitourinary tumors. Among the platinum-based anticancer drugs, Cisplatin (cis-diamine dichloroplatinum (II), cis-[Pt(NH3)2Cl2]) is one of the most potent components of cancer chemotherapy. The nephrotoxicity, neurotoxicity and ototoxicity, and platinum compounds associated resistant cancer are some major disadvantages. With the rapidly growing interest in platinum (II) complexes in tumor chemotherapy, researchers have synthesized many new platinum analogs as anticancer agents that show better cytotoxicity, and less off-target effects with less cellular resistance. This follows the introduction of oxaliplatin, water-soluble carboplatin, multinuclear platinum and newly synthesized complexes, etc. Methods: This review emphasizes recent advancements in drug design and development, the mechanism of platinum (II) complexes, their stereochemistry, current updates, and biomedical applications of platinum-based anticancer agents. In the last few decades, the popularity of platinum complexes as potent anti-cancer agents has risen as scientists have synthesized many new platinum complexes that exhibit better cytotoxicity coupled with less off-target effects.

Genetic Reduction of Mitochondria Complex I Subunits is Protective against Cisplatin-Induced Neurotoxicity in Drosophila.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anticancer agents. There are few predictable risk factors with which to identify susceptible patients. Effective preventive measures or treatments are not available. Here, we have used a model of CIPN in Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for the creation of RNAi lines, is resistant to cisplatin damage compared with the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplatin. The mitochondria of attP40 flies function similarly to control attP2 mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but attP40 mitochondria are able to retain function and even increase basal respiration rates in response to this stress. This retained mitochondrial activity is likely mediated by Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α, and is key to cisplatin resistance. Our findings represent the potential for both identification of susceptible patients and prevention of CIPN through the targeting of mitochondria.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy is a major, debilitating side effect of many platinum-based cancer drugs. There are few available screening tools to identify patients at risk, and there are no effective treatments. Here, we report a novel genetic change that confers resistance to cisplatin-induced neurotoxicity in a Drosophila model while preserving the toxic effect in rapidly dividing cells. This work has the potential to influence patient susceptibility testing and development of novel CIPN preventive treatments.

Intracellular Localization Studies of the Luminescent Analogue of an Anticancer Ruthenium Iminophosphorane with High Efficacy in a Triple-Negative Breast Cancer Mouse Model.

The potential of ruthenium(II) compounds as an alternative to platinum-based clinical anticancer agents has been unveiled after extensive research for over 2 decades. As opposed to cisplatin, ruthenium(II) compounds have distinct mechanisms of action that do not rely solely on interactions with DNA. In a previous report from our group, we described the synthesis, characterization, and biological evaluation of a cationic, water-soluble, organometallic ruthenium(II) iminophosphorane (IM) complex of p-cymene, ([(η6-p-cymene)Ru{(Ph3P═N-CO-2N-C5H4)-κ-N,O}Cl]Cl (1 or Ru-IM), that was found to be highly cytotoxic against a panel of cell lines resistant to cisplatin, including triple-negative breast cancer (TNBC) MDA-MB-231, through canonical or caspase-dependent apoptosis. Studies on a MDA-MB-231 xenograft mice model (after 28 days of treatment) afforded an excellent tumor reduction of 56%, with almost negligible systemic toxicity, and a favored ruthenium tumor accumulation compared to other organs. 1 is known to only interact weakly with DNA, but its intracellular distribution and ultimate targets remain unknown. To gain insight on potential mechanisms for this highly efficacious ruthenium compound, we have developed two luminescent analogues containing the BOPIPY fluorophore (or a modification) in the IM scaffold with the general structure of [(η6-p-cymene)Ru{(BODIPY-Ph2P═N-CO-2-NC5H4)-κ-N,O}Cl]Cl {BODIPY-Ph2P = 8-[(4-diphenylphosphino)phenyl]-4,4-dimethyl-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3a) and 4,4-difluoro-8-[4-[[2-[4-(diphenylphosphino)benzamido]ethyl]carbamoyl]phenyl]-1,3,5,7-tetramethyl,2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3b)}. We report on the synthesis, characterization, lipophilicity, stability, luminescence properties, and cell viability studies in the TNBC cell line MDA-MB-231, nonmalignant breast cells (MCF10a), and lung fibroblasts (IMR-90) of the new compounds. The ruthenium derivative 3b was studied by fluorescence confocal microscopy. These studies point to a preferential accumulation of the compound in the endoplasmic reticulum, mitochondria, and lysosomes. Inductively coupled plasma optical emission spectrometry (ICP-OES) analysis also confirms a greater ruthenium accumulation in the cytoplasmic fraction, including endoplasmic reticulum and lysosomes, and a smaller percentage of accumulation in mitochondria and the nucleus. ICP-OES analysis of the parent compound 1 indicates that it accumulates preferentially in the mitochondria and cytoplasm. Subsequent experiments in 1-treated MDA-MB-231 cells demonstrate significant reactive oxygen species generation.

Integrating of lipophilic platinum(IV) prodrug into liposomes for cancer therapy on patient-derived xenograft model

Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, cholesPt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of CholesPt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, CholesPt(IV)-Liposomes showed a small particle size (105.6 nm), the rapid release of platinum (Pt) ions, and notable apoptosis of cancer cells. In addition, according to the fluidity and safety results of animal experiments in mice, CholesPt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patient-derived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.

Recent advances in precision medicine for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality worldwide. Although advances in systemic chemotherapy for PDAC have improved survival outcomes for patients with the disease, chemoresistance is a major treatment issue for unselected PDAC patient populations. The existence of heterogeneity caused by a mixture of tumor cells and stromal cells produces chemoresistance and limits the targeted therapy of PDAC. Advances in precision medicine for PDACs according to the genetics and molecular biology of this disease may represent the next alternative approach to overcome the heterogeneity of different patients and improve survival outcomes for this poor prognostic disease. The genetic alteration of PDAC is characterized by four genes that are frequently mutated (KRAS, TP53, CDKN2A, and SMAD4). Furthermore, several genetic and molecular profiling studies have revealed that up to 25% of PDACs harbor actionable alterations. In particular, DNA repair dysfunction, including cases with BRCA mutations, is a causal element of sensitivity to platinum‐based anti‐cancer agents and poly‐ADP ribose polymerase (PARP) inhibitors. A deep understanding of the molecular and cellular crosstalk in the tumor microenvironment helps to establish scientifically rational treatment strategies for cancers that show specific molecular profiles. Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.

Efficacy and Safety of Paclitaxel Combined With Cetuximab for Head and Neck Squamous Cell Carcinoma.

For recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), popular regimens containing platinum-based anticancer agents and immune checkpoint inhibitors are impractical for platinum-intolerant patients. Herein, the efficacy and safety of paclitaxel and cetuximab combination therapy in R/M SCCHN were evaluated. In this retrospective study, paclitaxel (80 mg/m2) and cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) were administered in 28-day cycles on days 1, 8, and 15. Thirty-eight patients were treated. The overall response and disease control rates of first-line therapy were 43% and 79%, respectively, while those of second-line and later therapies were 20% and 90%, respectively. The median progression-free and overall survival were 5.3 and 12.5 months, respectively. All adverse events were manageable, including grade 3/4 neutropenia and anaemia affecting 8-13% of patients. Paclitaxel and cetuximab combination therapy may be suitable for treating R/M SCCHN.