Phase II study of deoxyspergualin in metastatic breast cancer

Abstract

We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m2/d (dose level 0) and 13 at a dose of 2150 mg/m2/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50-0.99 x 10(9)/l) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4-65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.

The human HSP70 family of chaperones: where do we stand?

“…DSG binds to the C-terminal EEVD motif, that is the same site of binding to the TPR-domain cochaperones (Nadler et al 1998). DSG showed significant antitumor activity in mice (Plowman et al 1987), but in a phase II trial, it was inefficient against metastatic breast cancer resistant to frontline chemotherapy (Dhingra et al 1994). Since DSG has a very low bioavailability and poor stability, several analogs with improved properties were generated.…”

The G ProteinαChaperone Ric-8 as a Potential Therapeutic Target

“…Over 20 heat shock protein/cognate 90 or 70 (HSP/C 90/70) inhibitors are being evaluated as standalone or combination therapies against various cancers in later-stage clinical trials (Dhingra et al, 1994;Wadhwa et al, 2000;Schmitt et al, 2003Schmitt et al, , 2006Mitsiades et al, 2006;Trepel et al, 2010;Leu et al, 2011;Modi et al, 2011;Jhaveri et al, 2012;Koren et al, 2012;Pacey et al, 2012;Sidera and Patsavoudi, 2014). HSP/C 90/70 are ubiquitous cellular chaperones that work with cochaperones to fold a majority of cellular proteins, including Ga subunits (Nathan et al, 1997;Thulasiraman et al, 1999;Busconi et al, 2000;Vaiskunaite et al, 2001;Waheed and Jones, 2002;Echeverria et al, 2011) .…”

Targeting the Protein Quality Control (PQC) Machinery

“…It is used by i.v. infusion in several clinical trials in oncology [98] and allograft rejection [99] (the latter being more promising than the former). A second generation, inverted amide analog (2.33, tresperimus) [100] shows better stability and bioavailability, with good clinical results in allograft rejection [101].…”