A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors

Janjigian, Yelena Y.; Lee, Wooin; Kris, Mark G.; Miller, Vincent A.; Krug, Lee M.; Azzoli, Christopher G.; Senturk, Emir; Calcutt, M. Wade; Rizvi, Naiyer A.

doi:10.1007/s00280-009-1088-4

Cited by 53 publications

(49 citation statements)

References 10 publications

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“…13) and in the United States (through National Cancer Institute; refs. 14,15), and is about to enter phase II studies against both solid tumors and hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity

et al. 2010

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The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an interstrand crosslink. The mean in vitro cytotoxic potency of SG2285 against human tumor cell lines is GI 50 20 pmol/L. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD 50 was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic, and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced-stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development. Cancer Res; 70(17); 6849-58. ©2010 AACR.

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“…13) and in the United States (through National Cancer Institute; refs. 14,15), and is about to enter phase II studies against both solid tumors and hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity

et al. 2010

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“…Following the demonstration of potent antitumour activity in vitro and in vivo, SG2000 (SJG-136) was the first pyrrolobenzodiazepine dimer to enter clinical trials [15][16][17] and it is in Phase II clinical evaluation in the USA and Europe. The current study shows that the extended dimer SG2057 containing a pentyldioxy, rather than a propyldioxy, linkage is more active in vitro than SG2000 and has superior efficacy in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…1a), was demonstrated to have significant in vitro and in vivo antitumor activity [13,14]. It has recently completed Phase I clinical trials in the UK (through Cancer Research UK [15]) and in the USA (through NCI [16,17]) and is in Phase II studies against both solid tumors and hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057

et al. 2011

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The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. SG2000 is a propyldioxy linked PBD dimer which binds sequence selectively in the minor groove of DNA forming DNA interstrand and intrastrand cross-linked adducts, and also mono-adducts depending on sequence. SG2057 is the corresponding dimer containing a pentyldioxy linkage. SG2057 has multilog differential in vitro cytotoxicity against a panel of human tumour cell lines with a mean GI(50) of 212 pM. The agent is highly efficient at producing DNA interstrand cross-links in cells which form rapidly and persist over a 48 h period. Significant antitumor activity was demonstrated in several human tumor xenograft models. Cures were obtained in a LOX-IMVI melanoma model following a single administration and dose-dependent activity, including regression responses, observed in SKOV-3 ovarian and HL-60 promyelocytic leukemia models following repeat dose schedules. In the advanced stage LS174T model, SG2057 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development.

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“…preference for purine-GATC-pyrimidine sequences (5)(6)(7). SJG-136 is extremely potent and showed cytotoxic effects at nM concentrations in a broad variety of tumor types in vitro and antitumor effects in xenograft models in vivo (5,8).…”

Section: Introductionmentioning

confidence: 99%

“…However, their interaction with ABC transporters is unknown. SJG-136 is the first PBD to enter clinical development and is currently being assessed in Phase II clinical trials (5,7,13).…”

Section: Introductionmentioning

confidence: 99%

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

Kaliszczak

Antonow

Patel

et al. 2010

AAPS J

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Abstract. Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA crosslinking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P-gp, ABCG2, and MRP1). Isogenic cell lines expressing P-gp and ABCG2, cell lines with acquired resistance to cytotoxic agents due to the high expression of ABC transporters, and specific inhibitors against P-gp, ABCG2, and MRP1 were used. P-gp and ABCG2 decreased the permeability of the PBD dimers across cell membranes and their interaction with DNA, reducing DNA damage and the overall cytotoxic effect. PBD monomer SG-2823 formed a conjugate with glutathione and interacted with MRP1, reducing its cytotoxic effect in A549 cells. Structure-activity relationship revealed that the interaction of PBDs with the transporters could be predicted considering the molecular weight, the lipophilicity, the number of (N+O) atoms and aromatic rings, the polar surface area, the hydrogen bonding energy, and electrophilic centers. A rational design of novel PBDs with increased potency and reduced interaction with the ABC transporters is proposed.

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A phase I trial of SJG-136 (NSC#694501) in advanced solid tumors

Cited by 53 publications

References 10 publications

SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity

SG2285, a Novel C2-Aryl-Substituted Pyrrolobenzodiazepine Dimer Prodrug That Cross-links DNA and Exerts Highly Potent Antitumor Activity

DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057

Optimization of the Antitumor Activity of Sequence-specific Pyrrolobenzodiazepine Derivatives Based on their Affinity for ABC Transporters

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