Abstract 5126: Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer
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Abstract Small cell lung cancer (SCLC) is an aggressive type of lung cancer and accounts for 10% to 15% of all lung cancer cases. The malignancy has a greater tendency to be widely disseminated by the time of diagnosis as well as to develop early resistance to conventional treatments, a cure is difficult to achieve. The current standard therapy for SCLC treatment, either with monotherapy (platinum based drugs) or combination therapy (e.g., cisplatin with irinotecan or topotecan), was shown to cause serious side effects and inevitably evoke drug resistance in a short time period. We have recently synthesized a series of novel bis(hydroxymethyl)indolizino[8,7-b]indole hybrids by fusing β-carboline and bis(hydroxymethyl)pyrrole moieties for antitumor evaluation. These hybrid molecules displayed diverse mechanisms of action involving topoisomerase II (Topo II) inhibition and induction of DNA cross-linking. Our results also showed that they significantly inhibited the cell growth of various human tumor cell lines. Of the tested tumor cell lines, the SCLC cells (H526 and H211) were the most susceptible to compounds BO-2239 and BO-2329. These hybrids induced cell cycle arrest at the G2/M phase and triggered tumor cell apoptotic death. Intriguingly, the substituent at N11 (H or Me) played a critical role in modulating Topo II inhibition and DNA cross-linking. Compared to the compounds with N11-Me group, derivatives having N11-H group profoundly increased Topo II inhibition activity but reduced DNA cross-linking activity. Among these hybrids, BO-2239 (with N11-H) was as potent as irinotecan, but more effective than cisplatin, in nude mice bearing SCLC H526 xenografts. Accordingly, hybrid BO-2239 may be further developed as a potential agent for the treatment of SCLC. Citation Format: Sue-Ming Chang, Ming-Hsi Wu, Hima Bindu Pidugu, Tsann-Long Su, Te-Chang Lee. Novel indolizino[8,7-b]indole hybrids with potent activity against small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5126. doi:10.1158/1538-7445.AM2017-5126Keywords:
Camptothecin
Topotecan
Topotecan
Clonogenic assay
Camptothecin
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Active metabolite
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The development of camptothecin-like compounds as inhibitors of DNA topoisomerase I for the treatment of solid tumors has generated clinical excitement in this new class of drugs. We have discovered, developed, and entered into clinical trial a novel, potent, and water-soluble camptothecin analog with significant antitumor activity. This compound, Gl147211C [7-(4-methylpiperaziinomethylene)-10, 11-ethylenedioxy-20(S)-camptothecin hydrochloride] is a specific inhibitor of DNA topoisomerase I. Compared to topotecan, Gl147211C is approximately three times as potent in the cleavable complex assay and approximately twice as soluble in aqueous medium. Human tumor cell line cytotoxicity assays indicated that Gl147211C was approximately 3- to 5-fold more potent than topotecan, while both compounds were relatively insensitive to the multidrug resistance P-glycoprotein. The in vivo preclinical antitumor activity of Gl147211C was compared to topotecan in an array of human tumor xenograft models in nude mice. In general, Gl147211C was able to induce regression of established tumors whereas topotecan was not. Microscopic evaluation of necropsied tissues indicated that drug-induced toxicity was mild, primarily limited to the gastrointestinal tract, and was comparable for both Gl147211C and topotecan. Based on these observations, Gl147211C moved through preclinical development and subsequently into Phase I clinical trial. A summary of Phase I trial results to date is provided.
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Camptothecin analogues such as topotecan increase the number of covalent topoisomerase I-DNA complexes, which, in turn, have been proposed to initiate apoptosis. If induction of apoptosis by the camptothecins is, in fact, dependent on the formation of topoisomerase I-DNA complexes, then it would be of clinical relevance to identify schedules of exposure to the camptothecins that maximize the formation of these complexes but minimize the total amount of the drug administered. The time and dose dependence of topoisomerase I-DNA complex formation was determined by incubating Daoy pediatric medulloblastoma cells in vitro with topotecan at concentrations equivalent to those achievable in the plasma clinically (10, 50, or 200 nM) and measuring the number of complexes present in cells incubated for 15 min to 48 h with the drug. Regardless of the concentration of topotecan used, covalent topoisomerase I-DNA complexes were maximal within 15 min following addition of the lactone form of topotecan to the tissue culture medium. After 2 h of exposure to topotecan, complexes had decreased from maximum to approximately half of that value. Few, if any, complexes were detectable with topotecan incubations of 24-48 h. Growth inhibition studies showed that the IC50s of topotecan for the Daoy cell line (2.2 x 10(-9) M) and also for a second pediatric medulloblastoma cell line, SJ-Med3 (3.6 x 10(-9) M), exposed to topotecan 8 h daily for 5 days or continuous exposure were equivalent. The decrease in topoisomerase I-DNA complexes between 15 min and 1 h was consistent with a pH-dependent re-equilibration of topotecan to the less active hydroxyacid form of the drug. The decrease in complexes after a 2-48-h incubation with the drug was attributable neither to biological inactivation of topotecan as shown by sequential growth inhibition studies nor to a decrease in amount of topoisomerase I in the drug-treated cells. Indirect immunofluorescence labeling of topoisomerase I in Daoy cells incubated for 48 h with 10 nM topotecan showed a redistribution of nucleolar topoisomerase I. We are currently evaluating the antitumor effect of intermittent repetitive exposures to topotecan in mice bearing Daoy cells as a xenograft. The clinical utility of each effective schedule of exposure will depend on whether the therapeutic index of repetitive intermittent exposure to the drug is more or less favorable than the therapeutic index of continuous exposure.
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Topotecan
Camptothecin
SN-38
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Combining antineoplastic analogues may increase efficacy by increasing the serum and intracellular concentration of the cytotoxic moiety shared by the analogues. Topotecan and irinotecan are two camptothecan analogues that are active in different human tumors (topotecan in ovary; irinotecan in colon) and in different experimental tumor systems. These data suggest that different mechanisms of drug resistance may be operative for the two agents, and if incomplete cross-resistance exists between analogues, concomitant administration may be advantageous. The objectives of this phase I study were 1) to determine in a phase trial design whether topotecan and irinotecan administered concomitantly on a weekly schedule can be delivered at the same dose intensity as that of single-agent topotecan or irinotecan delivery; and 2) to determine whether hematologic and/or nonhematologic toxicity is increased with topotecan and irinotecan administered together as a prelude to a possible phase II trial in responsive tumor categories. Irinotecan was administered for 30 to 45 minutes weekly × 4 at four dose levels: 50, 75, 100, and 125 mg/m2/wk. Topotecan was administered for 30 minutes (after irinotecan administration) at two dose levels within each of the irinotecan dose levels (1.0 and 1.5 mg/m2). Concomitant single-dose granulocytemacrophage colony-stimulating factor (G-CSF) was used for leukocyte counts between 1,000 cells/mm3 and 3,500 cells/mm3 to maintain schedule. Maximum tolerated dosage (MTD) for the topotecan and irinotecan combination was defined as that which permitted 4 weeks of topotecan and irinotecan administration with G-CSF at or near the dose intensity reported for each single agent. Twenty-one patients received 32 4-week cycles. Dose-limiting toxicity was hematologic with grade IV leukopenia and neutropenia occurring at all dose levels. There was no apparent increase in the diarrhea syndrome associated with irinotecan. The MTD for irinotecan (at 125 mg/m2/wk) is the same MTD as with single-agent irinotecan use. The MTD for concomitant topotecan (1.5 mg/m2/wk) is 60% of the single-agent topotecan dose for the 5-day topotecan schedule (at 2.5 mg/m2/wk) but only 30% of the single-agent topotecan dose for the weekly schedule (5 mg/m2/wk). The topoisomerase I inhibitor dose is increased minimally when the analogues are administered concomitantly on a weekly schedule. Comparative trials of single-agent topotecan and irinotecan versus the combination of topotecan and irinotecan would be necessary to provide the proof of principle that combining analogues can increase therapeutic effectiveness.
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The number of patients who make it to receive third-line chemotherapy is increasing owing to the improvements in adverse-event management of chemotherapy for small-cell lung cancer (SCLC). Sequencing of optimal treatment for SCLC is still a challenge for oncologists. In this paper, we aim to present a different approach to the treatment of SCLC.Between January 2008 and July 2014, all patients diagnosed with extensive-stage SCLC and treated with third-line chemotherapy at Gaziantep University Oncology Hospital were analyzed retrospectively. Disease control rates and progression-free survival (PFS) for first-, second-, and third-line chemotherapy, and overall survival (OS) were recorded. Survival analysis was calculated by using Kaplan-Meier method.A total of 255 SCLC patients were screened, and 25 of those patients who received third-line chemotherapy were included in this study. Median age was 57±10.131 years (range: 39-74 years). Disease control rates at first-, second-, and third-line chemotherapy were 92%, 68%, and 44%, respectively. Fourteen patients received irinotecan followed by topotecan, and eleven patients received topotecan followed by irinotecan. Second-line median PFS was statistically better in patients treated with irinotecan at second-line compared with those treated with topotecan (21 vs 12 weeks, P=0.018). Comparison of third-line median PFS of the two groups was not statistically significant (14 vs 12 weeks, P=0.986). Median OS was not statistically significant in patients who received irinotecan followed by topotecan vs those who received topotecan followed by irinotecan (18 vs 14 months, P=0.112).Sequential monotherapy with topotecan and irinotecan provides a considerable contribution to OS, and second-line irinotecan showed a better PFS, despite a similar OS, compared with topotecan.
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Camptothecin
Topoisomerase inhibitor
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Camptothecin
Topotecan
SN-38
Comet Assay
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Irinotecan (Camptosar, CPT-11), a member of the camptothecin family, represents the most active camptothecin available for clinical use today. Irinotecan is a topoisomerase I inhibitor. Topoisomerase enzymes support the topologic structure of DNA, thus facilitating translation and transcription. The enzyme topoisomerase I plays a crucial role in the relegation of single-strand breaks and in relieving torsional DNA stress.[1,2] Irinotecan and other camptothecin analogs interfere in this process by stabilizing the topoisomerase I/DNA cleavable complex.[2] This process is not compatible with prolonged cell survival.
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Topotecan is a semisynthetic water soluble analogue of camptothecin, which exerts its cytotoxic effects through inhibition of the enzyme topoisomerase I. This enzyme relaxes supercoiled DNA by covalently binding to it, leading to transient single-strand breaks that are resealed by topoisomerase I
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