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Franco Muggia

Publications and source records attributed to Franco Muggia.

22 records · Page 2Linked to original sources
PubMed2002

Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study.

The primary aims of this study were to evaluate the timecourse and dose response of microtubule bundle formationin peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4-59.2 mg/m(2)), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC((0-24)) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADPribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of beta-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS-247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer.

We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival.

Adenocarcinoma↗