Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer.
Expression of the Bcl-2 protein confers resistance to chemotherapy-mediated apoptotic signals in patients with breast cancer. We investigated effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies. Oblimersen targets Bcl-2 messenger RNA (mRNA), down-regulates Bcl-2 protein translation and enhances antitumor effects of subtherapeutic chemotherapy doses. Within a phase I trial, we administered escalating doses of oblimersen (3, 5 or 7 mg/kg/day) as continuous infusion on days 1-7 in combination with standard-dose docetaxel (Taxotere), Adriamycin and cyclophosphamide (TAC) on day 5 as preoperative chemotherapy in 28 patients with T2-4 tumors. Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells (PBMCs) 4 days after start of oblimersen and before TAC treatment by quantitative microfluidic real-time PCR. Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 putative predictive markers. Two of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day. PBMCs could not be evaluated as a surrogate tissue because no qualified RNA could be isolated. Nevertheless, we demonstrated feasibility to process clinical samples and to obtain good quality RNA from tumor biopsies and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer.
Rom
J
J
Department of Gynecology and Obstetrics, University of Heidelberg, Germany. joachim.rom@med.uni-heidelberg.de
von Minckwitz
G
G
Marmé
F
F
Ataseven
B
B
Kozian
D
D
Sievert
M
M
Schlehe
B
B
Schuetz
F
F
Scharf
A
A
Kaufmann
M
M
Sohn
C
C
Schneeweiss
A
A
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000627:therapeutic use; D000077143:Docetaxel; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D019254:Genes, bcl-2 / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D057234:Preoperative Period; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000627:therapeutic use; D013873:Thionucleotides / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D004317:Doxorubicin; C408162:oblimersen; D003520:Cyclophosphamide