Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG)

Pavlidis, Nicholas; Aamdal, Steinar; Awada, Ahmad; Calvert, Hilary; Fumoleau, P.; Sorio, Roberto; Punt, C. J. A.; Verweij, Jaap; Oosterom, Allan Van; Morant, Rudolf; Wanders, J.; Hanauske, Axel R.

doi:10.1007/s002800000134

Cited by 38 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This class of compounds binds to the minor groove in DNA and subsequently alkylates specific adenine residues via ring opening of their cyclopropyl group, which eventually leads to cell death (11). Several synthetic duocarmycin analogs have been taken into development, but they all failed in the clinic or before as a consequence of a limited TI (17)(18)(19).…”

Section: Design and Preparation Of Syd983mentioning

confidence: 99%

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Dokter

Ubink

Lee

et al. 2014

Molecular Cancer Therapeutics

143

125

View full text Add to dashboard Cite

A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody-drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology. Mol Cancer Ther; 13(11); 2618-29. Ó2014 AACR.

show abstract

Section: Design and Preparation Of Syd983mentioning

confidence: 99%

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Dokter

Ubink

Lee

et al. 2014

Molecular Cancer Therapeutics

143

125

View full text Add to dashboard Cite

show abstract

“…Several analogues have shown antitumor activity in preclinical models (22), and four (adozelesin, carzelesin, bizelesin, and KW-2189) were evaluated clinically. All lacked antitumor activity at their maximum tolerated doses (MTD), which were limited by myelotoxicity to which humans seemed to be considerably more sensitive than mice (23). We have developed synthetic analogues of the cyclopropylindolines in which the key phenol of the alkylating subunit is replaced by an amino functional group (aminochloromethylindolines; refs.…”

Section: Introductionmentioning

confidence: 99%

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

Wilson

Stribbling

Pruijn

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Hypoxia represents an important therapeutic target in tumors because of the resistance of hypoxic cells to radiotherapy and chemotherapy and because it is more severe in many tumors than in normal tissues. Here, we describe a class of prodrugs, nitro-chloromethylindolines, which undergo hypoxia-selective activation by endogenous nitroreductases in tumor cells to form the corresponding amino compounds. The latter are chemically related to the cyclopropylindoline antitumor antibiotics and they share the same properties of sequence-selective DNA minor groove alkylation and high cytotoxic potency. Of three alkylating subunits investigated, the chloromethylbenzindoline (CBI) structure provided the most favorable prodrug properties: aerobic cytotoxic potency of the amines was approximately 90-to 3,000-fold higher than the corresponding nitro compounds, and the nitro compounds showed air/anoxia potency differentials of up to 300-fold. Selective alkylation of adenine N3 in calf thymus DNA by an amino-CBI was shown by characterization of the thermal depurination product; the same adduct was shown in hypoxic RIF-1 cells exposed to the corresponding nitro-CBI prodrug under hypoxic (but not oxic) conditions. The amino metabolite generated from a nitro-CBI by cells expressing Escherichia coli nfsB nitroreductase in multicellular layer cultures was shown to elicit bystander killing of surrounding cells. Nitro-CBI prodrugs were >500-fold less toxic to mice than amino-CBIs by i.p. administration and provided selective killing of hypoxic cells in RIF-1 tumors (although only at maximally tolerated doses). Nitro-CBIs are novel lead hypoxia-activated prodrugs that represent the first examples of hypoxiaselective generation of potent DNA minor groove alkylating agents.

show abstract

“…Bizelesin and adozelesin of the cyclopropylpyrroleindole family are two novel anticancer drugs with these properties (4, 6 -10). These sequence-specific cyclopropylpyrroleindole drugs, as well as several other AT-specific MGBs, are currently in phase I clinical trials (11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

AT-rich Islands in Genomic DNA as a Novel Target for AT-specific DNA-reactive Antitumor Drugs

Woynarowski¹,

Treviño²,

Rodriguez³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Interstrand cross-links at T(A/T) 4 A sites in cellular DNA are associated with hypercytotoxicity of an anticancer drug, bizelesin. Here we evaluated whether these lethal effects reflect targeting critical genomic regions. An in silico analysis of human sequences showed that T(A/T) 4 A motifs are on average scarce and scattered. However, significantly higher local motif densities were identified in distinct minisatellite regions (200 -1000 base pairs of ϳ85-100% AT), herein referred to as "AT islands." Experimentally detected bizelesin lesions agree with these in silico predictions. Actual bizelesin adducts clustered within the model AT island naked DNA, whereas motif-poor sequences were only sparsely adducted. In cancer cells, bizelesin produced high levels of lesions (ϳ4.7-7.1 lesions/kilobase pair/M drug) in several prominent AT islands, compared with markedly lower lesion levels in several motif-poor loci and in bulk cellular DNA (ϳ0.8 -1.3 and ϳ0.9 lesions/kilobase pair/M drug, respectively). The identified AT islands exhibit sequence attributes of matrix attachment regions (MARs), domains that organize DNA loops on the nuclear matrix. The computed "MAR potential" and propensity for supercoiling-induced duplex destabilization (both predictive of strong MARs) correlate with the total number of bizelesin binding sites. Hence, MAR-like ATrich non-coding domains can be regarded as a novel class of critical targets for anticancer drugs.

show abstract

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG)

Abstract: At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Cited by 38 publications

References 0 publications

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

AT-rich Islands in Genomic DNA as a Novel Target for AT-specific DNA-reactive Antitumor Drugs

Contact Info

Product

Resources

About