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Fulltext Molecular responses during chemotherapy in acute myeloid leukemias in predicting poor-response to standard chemotherapy

Maha A, Cheong SK, Leong CF, Seow HF

Malays J Pathol, 2009 Dec;31(2):81-91.
PMID: 20514850 MyJurnal

Signal transduction pathways are constitutively expressed in leukaemic cells resulting in aberrant survival of the cells. It is postulated that in cells of chemo-sensitive patients, chemotherapy induces apoptotic signals leading to cell death while survival signals are maintained in cells of chemo-resistant patients. There is very little information currently, on the expression of these mediators in patients immediately after chemotherapy initiation. We examined the expression pattern of proinflammatory cytokines, signaling molecules of the PI3K and MAPK pathways molecules and death receptor, DR5 on paired samples at diagnosis and during chemotherapy in acute myeloid leukaemia patients treated with cytosine arabinoside and daunorubicin. The results were correlated with remission status one month after chemotherapy. We found that in chemo-sensitive patients, chemotherapy significantly increased the percentage of cases expressing TNF-alpha (p = 0.025, n = 9) and IL-6 (p = 0.002, n = 11) compared to chemo-resistant cases. We also observed an increased percentage of chemo-sensitive cases expressing DR5 and phosphorylated p38, and Jnk. Thus, expression of TNF-alpha, IL-6, DR5, phospho-p38 and phospho-Jnk may regulate cell death in chemo-sensitive cases. In contrast, a significantly higher percentage of chemo-resistant cases expressed phospho-Bad (p = 0.027, n = 9). IL-beta and IL-18 were also found to be higher in chemo-resistant cases at diagnosis and during chemotherapy. Thus, expression of various cellular molecules in leukaemic blasts during chemotherapy may be useful in predicting treatment outcome. These cellular molecules may also be potential targets for alternative therapy.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Chalcones with electron-withdrawing and electron-donating substituents: anticancer activity against TRAIL resistant cancer cells, structure-activity relationship analysis and regulation of apoptotic proteins

Mai CW, Yaeghoobi M, Abd-Rahman N, Kang YB, Pichika MR

Eur J Med Chem, 2014 Apr 22;77:378-87.
PMID: 24675137 DOI: 10.1016/j.ejmech.2014.03.002

In the present study, a series of 46 chalcones were synthesised and evaluated for antiproliferative activities against the human TRAIL-resistant breast (MCF-7, MDA-MB-231), cervical (HeLa), ovarian (Caov-3), lung (A549), liver (HepG2), colorectal (HT-29), nasopharyngeal (CNE-1), erythromyeloblastoid (K-562) and T-lymphoblastoid (CEM-SS) cancer cells. The chalcone 38 containing an amino (-NH2) group on ring A was the most potent and selective against cancer cells. The effects of the chalcone 38 on regulation of 43 apoptosis-related markers in HT-29 cells were determined. The results showed that 20 apoptotic markers (Bad, Bax, Bcl-2, Bcl-w, Bid, Bim, CD40, Fas, HSP27, IGF-1, IGFBP-4, IGFBP-5, Livin, p21, Survivin, sTNF-R2, TRAIL-R2, XIAP, caspase-3 and caspase-8) were either up regulated or down regulated.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Curcumin Sensitizes Cancers Towards TRAIL-induced Apoptosis via Extrinsic and Intrinsic Apoptotic Pathways

Ngai SC

Curr Drug Targets, 2020;21(9):849-854.
PMID: 32116190 DOI: 10.2174/1389450121666200302124426

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a natural protein expressed in a wide range of tissues in our body. It is a promising anti-cancer agent due to its selective killing of cancer cells, rendering normal cells unharmed. However, resistance occurs either intrinsically or develops over the course of TRAIL treatment. In view of its specificity to cancer cells, there is a pushing need to overcome TRAIL resistance. Curcumin (Cur), a natural active constituent of turmeric, has been evidenced to have anti-cancer properties. However, it is limited by its sparing solubility and low bioavailability. Combinational therapy is one of the most frequently used strategies to overcome these limitations, which has been proved to be more effective than monotherapy by achieving synergistic effects and reducing toxicity. This review aims to discuss TRAIL and its underlying apoptotic mechanisms, the combinational treatment of Cur and TRAIL in view of their respective limitations, and the underlying apoptotic mechanisms activated by the sensitization of cancers by Cur towards TRAIL-induced apoptosis. Finally, this review discusses the research gap and the author's insight into this research area in bridging the research gap from bench to bedside.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Fulltext Down-Regulation of MicroRNA-210 Confers Sensitivity towards 1'S-1'-Acetoxychavicol Acetate (ACA) in Cervical Cancer Cells by Targeting SMAD4

Phuah NH, Azmi MN, Awang K, Nagoor NH

Mol Cells, 2017 Apr;40(4):291-298.
PMID: 28401751 DOI: 10.14348/molcells.2017.2285

MicroRNAs (miRNAs) are short non-coding RNAs that regulate genes posttranscriptionally. Past studies have reported that miR-210 is up-regulated in many cancers including cervical cancer, and plays a pleiotropic role in carcinogenesis. However, its role in regulating response towards anti-cancer agents has not been fully elucidated. We have previously reported that the natural compound 1'S-1'-acetoxychavicol acetate (ACA) is able to induce cytotoxicity in various cancer cells including cervical cancer cells. Hence, this study aims to investigate the mechanistic role of miR-210 in regulating response towards ACA in cervical cancer cells. In the present study, we found that ACA down-regulated miR-210 expression in cervical cancer cells, and suppression of miR-210 expression enhanced sensitivity towards ACA by inhibiting cell proliferation and promoting apoptosis. Western blot analysis showed increased expression of mothers against decapentaplegic homolog 4 (SMAD4), which was predicted as a target of miR-210 by target prediction programs, following treatment with ACA. Luciferase reporter assay confirmed that miR-210 binds to sequences in 3'UTR of SMAD4. Furthermore, decreased in SMAD4 protein expression was observed when miR-210 was overexpressed. Conversely, SMAD4 protein expression increased when miR-210 expression was suppressed. Lastly, we demonstrated that overexpression of SMAD4 augmented the anti-proliferative and apoptosis-inducing effects of ACA. Taken together, our results demonstrated that down-regulation of miR-210 conferred sensitivity towards ACA in cervical cancer cells by targeting SMAD4. These findings suggest that combination of miRNAs and natural compounds could provide new strategies in treating cervical cancer.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Fulltext Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer

Abdullah NA, Inman M, Moody CJ, Storr SJ, Martin SG

Invest New Drugs, 2021 10;39(5):1232-1241.
PMID: 33768386 DOI: 10.1007/s10637-021-01106-5

Radiotherapy is an effective treatment modality for breast cancer but, unfortunately, not all patients respond fully with a significant number experiencing local recurrences. Overexpression of thioredoxin and thioredoxin reductase has been reported to cause multidrug and radiation resistance - their inhibition may therefore improve therapeutic efficacy. Novel indolequinone compounds have been shown, in pancreatic cancer models, to inhibit thioredoxin reductase activity and exhibit potent anticancer activity. The present study evaluates, using in vitro breast cancer models, the efficacy of a novel indolequinone compound (IQ9) as a single agent and in combination with ionising radiation using a variety of endpoint assays including cell proliferation, clonogenic survival, enzyme activity, and western blotting. Three triple-negative breast cancer (MDA-MB-231, MDA-MB-468, and MDA-MB-436) and two luminal (MCF-7 and T47D) breast cancer cell lines were used. Results show that treatment with IQ9 significantly inhibited thioredoxin reductase activity, and inhibited cell growth and colony formation of breast cancer cells with IC50 values in the low micromolar ranges. Enhanced radiosensitivity of triple-negative breast cancer cells was observed, with sensitiser enhancement ratios of 1.20-1.43, but with no evident radiosensitisation of luminal breast cancer cell lines. IQ9 upregulated protein expression of thioredoxin reductase in luminal but not in triple-negative breast cancer cells which may explain the observed differential radiosensitisation. This study provides important evidence of the roles of the thioredoxin system as an exploitable radiobiological target in breast cancer cells and highlights the potential therapeutic value of indolequinones as radiosensitisers.***This study was not part of a clinical trial. Clinical trial registration number: N/A.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
A review on ethnobotany, pharmacology and phytochemistry of Tabernaemontana corymbosa

Abubakar IB, Loh HS

J Pharm Pharmacol, 2016 Apr;68(4):423-32.
PMID: 26887962 DOI: 10.1111/jphp.12523

OBJECTIVES: Tabernaemontana is a genus from the plant family, Apocynaceae with vast medicinal application and widespread distribution in the tropics and subtropics of Africa, Americas and Asia. The objective of this study is to critically evaluate the ethnobotany, medicinal uses, pharmacology and phytochemistry of the species, Tabernaemontana corymbosa (Roxb. ex Wall.) and provide information on the potential future application of alkaloids isolated from different parts of the plant.
KEY FINDINGS: T. corymbosa (Roxb. ex Wall.) parts are used as poultice, boiled juice, decoctions and infusions for treatment against ulceration, fracture, post-natal recovery, syphilis, fever, tumours and orchitis in Malaysia, China, Thailand and Bangladesh. Studies recorded alkaloids as the predominant phytochemicals in addition to phenols, saponins and sterols with vast bioactivities such as antimicrobial, analgesic, anthelmintic, vasorelaxation, antiviral and cytotoxicity.
SUMMARY: An evaluation of scientific data and traditional medicine revealed the medicinal uses of different parts of T. corymbosa (Roxb. ex Wall.) across Asia. Future studies exploring the structure-bioactivity relationship of alkaloids such as jerantinine and vincamajicine among others could potentially improve the future application towards reversing anticancer drug resistance.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Fulltext Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells

Nalairndran G, Chung I, Abdul Razack AH, Chung FF, Hii LW, Lim WM, et al.

J Cell Mol Med, 2021 Sep;25(17):8187-8200.
PMID: 34322995 DOI: 10.1111/jcmm.16684

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Aspidofractinine and Eburnane Alkaloids from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused, and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora

Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS

J Nat Prod, 2016 Jan 22;79(1):230-9.
PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992

Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Corynanthean, eburnan, secoleuconoxine, and pauciflorine alkaloids from Kopsia pauciflora

Gan CY, Yoganathan K, Sim KS, Low YY, Lim SH, Kam TS

Phytochemistry, 2014 Dec;108:234-42.
PMID: 25442910 DOI: 10.1016/j.phytochem.2014.09.014

Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine-resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla

Lim SH, Low YY, Sinniah SK, Yong KT, Sim KS, Kam TS

Phytochemistry, 2014 Feb;98:204-15.
PMID: 24342109 DOI: 10.1016/j.phytochem.2013.11.014

A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*
Rhazinilam-Leuconolam-Leuconoxine Alkaloids from Leuconotis griffithii

Gan CY, Low YY, Thomas NF, Kam TS

J Nat Prod, 2013 May 24;76(5):957-64.
PMID: 23647487 DOI: 10.1021/np400214y

Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Strychnan and secoangustilobine A type alkaloids from Alstonia spatulata. Revision of the C-20 configuration of scholaricine

Tan SJ, Low YY, Choo YM, Abdullah Z, Etoh T, Hayashi M, et al.

J Nat Prod, 2010 Nov 29;73(11):1891-7.
PMID: 21043460 DOI: 10.1021/np100552b

A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Leucophyllidine, a cytotoxic bisindole alkaloid constituted from the union of an eburnan and a new vinylquinoline alkaloid

Gan CY, Robinson WT, Etoh T, Hayashi M, Komiyama K, Kam TS

Org. Lett., 2009 Sep 3;11(17):3962-5.
PMID: 19708704 DOI: 10.1021/ol9016172

A cytotoxic bisindole alkaloid possessing an unprecedented structure constituted from the union of an eburnan half and a novel vinylquinoline alkaloid has been isolated from Leuconotis griffithii. The structure was established by analysis of the spectroscopic data and confirmed by X-ray diffraction analysis. A possible biogenetic pathway to the novel quinolinic coupling partner is presented from an Aspidosperma precursor.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
A cycloartane incorporating a fused tetrahydrofuran ring and a cytotoxic lactam from Monocarpia marginalis

Lim SH, Mahmood K, Komiyama K, Kam TS

J Nat Prod, 2008 Jun;71(6):1104-6.
PMID: 18462006 DOI: 10.1021/np800123g

A new cycloartane, monocarpinine (1), incorporating a fused tetrahydrofuranyl ring, and a cytotoxic tetracyclic lactam, monomarginine (2), were isolated from a stem bark extract of the Malayan species Monocarpia marginalis. The structures of these compounds were determined using NMR and MS analysis. Monomarginine (2) showed appreciable cytotoxicity toward human KB (both drug-sensitive and drug-resistant) and Jurkat cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Biologically active aspidofractinine alkaloids from Kopsia singapurensis

Subramaniam G, Hiraku O, Hayashi M, Koyano T, Komiyama K, Kam TS

J Nat Prod, 2008 Jan;71(1):53-7.
PMID: 18078327

Ten new indole alkaloids of the aspidofractinine type, in addition to several recently reported indole alkaloids and 20 other known alkaloids, were obtained from the leaf and stem-bark extract of the Malayan Kopsia singapurensis, viz., kopsimalines A-E (1-5), kopsinicine (6), kopsofinone (7), and kopsiloscines H-J (8-10). The structures of these alkaloids were determined using NMR and MS analysis. Kopsimalines A (1), B (2), C (3), D (4), and E (5) and kopsiloscine J (10) were found to reverse multidrug-resistance in vincristine-resistant KB cells, with 1 showing the highest potency.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Biologically active aspidofractinine, rhazinilam, akuammiline, and vincorine alkaloids from Kopsia

Subramaniam G, Hiraku O, Hayashi M, Koyano T, Komiyama K, Kam TS

J Nat Prod, 2007 Nov;70(11):1783-9.
PMID: 17939738

Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Leuconoxine, kopsinitarine, kopsijasmine, and kopsinone derivatives from Kopsia

Lim SH, Sim KM, Abdullah Z, Hiraku O, Hayashi M, Komiyama K, et al.

J Nat Prod, 2007 Aug;70(8):1380-3.
PMID: 17608533

Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Macroline-Sarpagine Bisindole Alkaloids with Antiproliferative Activity from Alstonia penangiana

Yeap JS, Saad HM, Tan CH, Sim KS, Lim SH, Low YY, et al.

J Nat Prod, 2019 11 22;82(11):3121-3132.
PMID: 31642315 DOI: 10.1021/acs.jnatprod.9b00712

A methanol extract of the stem bark of the Malayan Alstonia penangiana provided seven new bisindole alkaloids, comprising six macroline-sarpagine alkaloids (angustilongines E-K, 1-6) and one macroline-pleiocarpamine bisindole alkaloid (angustilongine L, 7). Analysis of the spectroscopic data (NMR and MS) of these compounds led to the proposed structures of these alkaloids. The macroline-sarpagine alkaloids (1-6) showed in vitro growth inhibitory activity against a panel of human cancer cell lines, inclusive of KB, vincristine-resistant KB, PC-3, LNCaP, MCF7, MDA-MB-231, HT-29, HCT 116, and A549 cells (IC50 values: 0.02-9.0 μM).

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Mechanisms of tumor cell resistance to the current targeted-therapy agents

Khamisipour G, Jadidi-Niaragh F, Jahromi AS, Zandi K, Hojjat-Farsangi M

Tumour Biol., 2016 Aug;37(8):10021-39.
PMID: 27155851 DOI: 10.1007/s13277-016-5059-1

Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
Fulltext Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, et al.

Blood, 2019 02 07;133(6):530-539.
PMID: 30510080 DOI: 10.1182/blood-2018-09-876136

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Matched MeSH terms: Drug Resistance, Neoplasm/drug effects*

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