Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days

Dowlati, Afshin; Hoppel, Charles L.; Ingalls, Stephen T.; Majka, Susan M.; Li, Xin; Sedransk, Nell; Spiro, Timothy; Gerson, Stanton L.; Ivy, Percy; Remick, Scot C.

doi:10.1200/jco.2001.19.8.2309

Cited by 32 publications

(36 citation statements)

References 9 publications

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“…Significant interpatient variability was noted. Pharmacokinetic data from previous phase I trials showed that NSC 655649 exhibited dose-proportional kinetics over the dose range tested (11,12). Interestingly, Cl values for NSC 655649 were lower at the 550 mg/m 2 dose level in the present trial, which may explain the substantial increase in both severity and rate of toxicities at this NSC 655649 dose.…”

Section: Discussionmentioning

confidence: 43%

“…NSC 655649 is active against cancer cells with acquired resistance to etoposide and teniposide (5). In phase I studies, NSC 655649 has shown antitumor activity in gastrointestinal tumors as well as in taxane-and platinum-resistant ovarian cancer (11,12). The enhanced clinical benefit observed with NSC 655649 in a phase II trial served in part as the impetus for an ongoing phase III trial in advanced biliary cancers (14).…”

Section: Discussionmentioning

confidence: 99%

“…A higher proportion of patients had hepatic compromise at the NSC 655649 550 mg/m 2 dose level (9 of 11 total patients) compared with the 440 mg/m 2 cohort patients (3 of 7), although there were no statistical differences in the liver function tests. The principal mechanisms of NSC 655649 elimination are hepatic metabolism and biliary excretion (11,12). Renal clearance of the parent compound accounted for f2% of overall drug disposition (12).…”

Section: Discussionmentioning

confidence: 99%

“…In one study, neutropenia was the principal toxicity when NSC 655649 was administered at doses ranging from 60 to 188 mg/m 2 /d for 5 days (11). Two partial responses (PR) were noted in patients with cancers of the stomach and unknown primary.…”

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confidence: 99%

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Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors

Ricart¹,

Hammond²,

Kuhn

et al. 2005

Clinical Cancer Research

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Purpose:To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed. Experimental Design: NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m 2 . After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored. Results: Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/ CDDP dose level of 550/50 mg/m 2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses. Conclusions: NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m 2 , respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.

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Section: Discussionmentioning

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors

Ricart¹,

Hammond²,

Kuhn

et al. 2005

Clinical Cancer Research

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“…During in vitro studies, becatecarin was shown to be active against cell lines of Ewing sarcoma, medulloblastoma, neuroblastoma and rhabdomyosarcoma, [30] and it appeared to be a more potent anticancer drug than rebeccamycin itself when tested on a leukaemia cell line. [27] A range of promising Phase I clinical trials were carried out on becatecarin between 1996 and 2002, [31][32][33][34][35][36] but in a 2008 Phase II clinical study by Langevin et al on the effects of the drug on children with solid CNS tumours, it was revealed that myelosupression was a significant side effect, [37] effectively halting the development of this drug for use on this demographic.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

134

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HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

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Indolocarbazole Glycosides in Inactive Conformations

et al. 2003

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Indolocarbazole glycosides related to rebeccamycin represent a promising category of antitumor agents targeting DNA and topoisomerase I. These drugs prefer to adopt a closed conformation with an intramolecular hydrogen bond between the indole NH group and the pyranose oxygen atom. Three pairs of indolocarbazole monoglycosides bearing an NH or an N-methyl indole moiety were synthesized and their biological properties investigated at the molecular and cellular level. Replacing the indole NH proton with a methyl group reduces DNA interaction and abolishes activity against DNA topoisomerase I. Surface plasmon resonance studies performed with a pair of water-soluble indolocarbazole glycosides and two hairpin oligonucleotides containing an [AT]4 or a [CG]4 sequence indicate that both the NH and the N-methyl derivative maintain a relatively high affinity for DNA (Keq = 2 - 6 x 10(5) M(-1)) but the incorporation of the methyl group restricts access to the DNA. The number of ligand binding sites (n) on the oligonucleotides is about twice as high for the NH compound compared to its N-methyl analogue. Modeling and 1H NMR studies demonstrate that addition of the N-methyl group drives a radical change in conformation in which the orientation of the aglycone relative to the beta-glucoside is reversed. The loss of the closed conformation by the N-methyl derivatives perturbs thir ability to access DNA binding sites and prevents the drug from inhibiting topoisomerase I. As a consequence, the NH compounds exhibit potent cytotoxicity against CEM leukemia cells with an IC50 value in the 1 microM range, whereas the N-methyl analogues are 10 to 100 times less cytotoxic. These studies offer circumstantial evidence supporting the importance of the closed conformation in the interaction of indolocarbazole glycosides with their molecular targets, DNA and topoisomerase I.

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Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days

Abstract: The recommended phase II dose for NSC 665649 on a daily x 5 every 3 weeks schedule is 141 and 165 mg/m(2)/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.

Cited by 32 publications

References 9 publications

Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors

Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Indolocarbazole Glycosides in Inactive Conformations

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