ABSTRACT
This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/diagnosis , Aged , Boronic Acids/administration & dosage , Bortezomib , Cohort Studies , Cyclophosphamide/administration & dosage , Dexamethasone/administration & dosage , Female , Follow-Up Studies , Humans , Lenalidomide , Male , Maximum Tolerated Dose , Middle Aged , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Pyrazines/administration & dosage , Remission Induction , Survival Rate , Thalidomide/administration & dosage , Thalidomide/analogs & derivatives , Treatment OutcomeABSTRACT
Both 2,500- and 6,000-nucleotide (nt) mRNAs are generated by alternative splicing of the primary transcript from the human gene for choline acetyltransferase (ChAT), the 68-kDa enzyme that synthesizes acetylcholine. In vitro translation of cRNA derived from a clone of the 2,500-nt mRNA produced a protein with ChAT activity demonstrating that this transcript encodes the human ChAT enzyme. An antibody directed against a unique amino acid sequence predicted from the 6,000-nt ChAT gene transcript identified a 27-kDa protein on immunoblots of human nucleus basalis proteins. This protein was further shown to cross-react with antibodies prepared against the 68-kDa human ChAT enzyme. Gel-filtration chromatography of human nucleus basalis proteins demonstrated that the 27-kDa protein does not have ChAT activity, which eluted as a single peak coincident with that of the 68-kDa enzyme. The 27-kDa protein was, however, shown to colocalize with the ChAT enzyme in cholinergic neurons of the human spinal cord using immunohistochemical techniques.
