Showing papers by "Ruth Duncan published in 2009"

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer.

Abstract: Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase H studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m(2) doxorubicin-equivalent) were given i.v., together with I-123-labelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naive patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naive patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, Supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

Poly(amidoamine) Conjugates Containing Doxorubicin Bound via an Acid-Sensitive Linker

Abstract: Poly(amidoamine)s with amino pendant groups were prepared by hydrogen-transfer polyaddition of primary and secondary amines to bis-acrylamines. Dansyl cadaverine (DC) doxorubicin (Dox) were bound to the polymers via a cis-aconityl spacer to give conjugates containing 3 microg of DC per mg of polymer and 28 to 35 microg of Dox per mg of polymer. Release of DC and Dox at physiological and acidic pH varied from 0 to 35% over 48 h and was pH dependent. Although the ISA1Dox conjugate (IC(50) = 6 microg Dox x mL(-1)) presented similar toxicity as the parent polymer without Dox, ISA23Dox showed increased toxicity (IC(50) = 10 microg Dox x mL(-1)). These results suggest that ISA23Dox is able to release biologically active Dox in vitro and that this conjugate might be suitable for further development.

Preface PEGylated protein conjugates: A new class of therapeutics for the 21st century

Abstract: The collected Chapters in this volume describe the current status of poly(ethylene glycol) (PEG) modification of proteins, peptides, oligonucleotides and small molecule drugs, the recent advances in conjugation chemistry, and new clinical products. The book provides an excellent update in this rapidly evolving field, and the comprehensive collection of Chapters complements well past reviews/volumes that have documented the evolution of PEGylation. For example, a reader new to this field is encouraged to gain the historical perspective by reading the following reviews [1, 2, 3, 4, 5, 6, 7, 8]. Only then is it possible to see just how far this field has come and understand that it has already established a new class of therapeutics as we start the 21st Century!