Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors.

PURPOSE: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. RESULTS: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-na?ve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. CONCLUSIONS: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.     

Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot.

Our previous studies identified the extract of Beta vulgaris (beetroot), commercially also known as betanin, as a potent cancer chemopreventive agent in both in vitro Epstein-Barr early antigen activation assay and in an in vivo two-stage mouse lung and skin carcinogenesis. To explore this issue further, we have now investigated its cancer chemopreventive potentials in three different chemical carcinogen initiation-promotion experimental tumor models in mice. Following tumor initiation with 390 nmol of 7,12-dimethylbenz(a)anthracene (DMBA) in 100 microl of acetone, the mouse skin tumor promotion with 3430 J/m(2) of ultraviolet light-B (UV-B) as well as splenomegaly was significantly inhibited by oral administration of 0.0025% betanin. At the same dose, betanin also afforded significant protection in the mouse skin cancer model following the topical application of 390 nmol of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) in 100 microl of acetone and promoted by topical administration of 1.7 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA). In the two-stage model of hepatocarcinogenesis in mice with N-nitrosodiethylamine (DEN, 30 mg/kg) as the initiator and phenobarbital as the promoter, oral administration of 0.0025% betanin also showed a very significant inhibition of both the incidence and multiplicity of the liver tumors. These findings along with our initial reports suggest that betanin which is a regularly consumed natural product colorant is an effective cancer chemopreventive agent in mice. The most interesting observation is that the cancer chemopreventive effect was exhibited at a very low dose used in the study and thus indicating that beetroot warrants more attention for possible human applications in the control of malignancy.     

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071)

Purpose: 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. Method: This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2–0.68 mg/m² daily. Results: Grade 1–2 nausea (n=9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and C _max , and these parameters showed a poor correlation with dose (r ²=0.07 and 0.38, respectively). Conclusions: We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere. Received: 18 June 1997 / Accepted: 12 November 1997     

Dipyridamole modulates multidrug resistance and intracellular as well as nuclear levels of doxorubicin in B16 melanoma cells

Simultaneous occurrence of resistance to many chemothera-peutic agents, termed multidrug resistance (MDR), is a complex phenotype. MDR occurs due to several reasons, including over-expression of a 170-kDa membrane-bound protein, called P-glycoprotein (P-gp), which apparently participates in active drug efflux. Multidrug-resistant cells also frequently exhibit an altered pattern of intracellular drug distribution, resulting in a reduction in the nuclear level of drugs such as doxorubicin (DOX). In this study, the effect of dipyridamole (DP) on drug resistance and on intracellular as well as nuclear levels of DOX in multidrug-resistant melanoma cells has been examined. For this purpose, drug-sensitive murine melanoma cells (B16V) and their multidrug-resistant variant cells, (B16VDXR; selected for resistance to DOX) which over-produce P-gp, were employed. B16VDXR cells were cross-resistant to several anti-cancer agents including etoposide (VP-16) and mitoxantrone (Mitox). DP (10 m?M) significantly potentiated the cytotoxicity of DOX, VP-16 and Mitox towards multidrug-resistant B16VDXR cells but not in parental drug-sensitive B16V cells. The presence of DP resulted in a 3.7-fold increase in the total cellular level and a 4.2-fold increase in the nuclear content of DOX in the resistant cells. Isobologram analysis indicates that DP at several pharmacologically relevant concentrations synergistically potentiates the activity of DOX in B16VDXR cells.     

Prostatic infiltration in leukaemia and lymphoma

12 cases are reported in which the prostate was the site of a leukaemic or lymphomatous infiltration. Hodgkin's disease, not previously reported as involving the prostate, was seen in one instance. In all cases the diagnosis was made histologically. Although 5 patients were known to have leukaemia or lymphoma prior to surgery, the preoperative clinical diagnosis in 3 cases was benign prostatic hypertrophy and in 3 instances prostatic carcinoma. In 6 patients, the initial diagnosis of leukaemia or lymphoma was made on the prostatic specimen and in one instance infiltration was discovered at postmortem. The management of leukaemic and lymphomatous infiltration is discussed.     

Respiratory tract fistulae in recurrent aerodigestive cancers after chemotherapy

Bronchoesophageal fistulae, a form of respiratory tract fistula, occurred in four patients with squamous cell carcinoma arising in the esophagus or left bronchus after cytoreductive chemotherapy. All four had locoregional cancer, recurrent after high-dose external radiation therapy. Esophageal cancer was treated with sequential intravenous cisplatin 100 mg/m2 (day 1) and 5-fluorouracil (5-FU) 40 mg/m2/hour X 120 (days 2-7). Lung cancer was treated with sequential intravenous cisplatin 100 mg/m2 (day 1), 5-FU 40 mg/m2/hour X 72 (days 2-5), and etoposide 80 mg/m2/day X 3 (days 2, 3, and 4). All patients had symptomatic relief and tumor regression after oncolytic chemotherapy, which was well tolerated with no hematologic toxicity. After the second or third cycle of chemotherapy, bronchoesophageal fistula occurred in all four patients with manifestations of pneumonia, which proved fatal in two patients. The other two patients were effectively palliated for 14 and 36+ weeks after celestin tube placement. Bronchoesophageal fistula should be managed by antibiotics and respiratory support followed by elective placement of celestin tube in most patients and by esophageal exclusion or esophageal bypass in a few select patients. In aerodigestive cancers, respiratory tract fistula may be a rare and potentially fatal complication of chemotherapy induced tumor lysis.     

Primary Hyperparathyroidism–A Clinical,Biochemical and Radiological Profile with Emphasis on Geographical Variations

Clinical, biochemical and radiological features in 12 proven cases of primary hyperparathyroidism in Northern India are described. Occurrence of disease is in the younger age group and skeletal disease is present in 100% in such patients. Epiphyseal changes are recognized and Looser's zone presence indicates an associated vit D deficiency state. Hypercal-ciuria (more than 250 mg 24 hour) however was present in only 33%. On further analysis. alkaline phosphatase was raised markedly and above 40 KA units in 83^-6% instances. Chief cell adenomas were present in all instances. In one instance of pluriglandular syndrome, three adenomas have been removed. The phenomenon of hungry bones was met with often in this series. In recognition of skeletal lesions, calcium intake was not often below the minimum recommended intake, e.g. less than 400 mg per 24 hours, nor was the duration of disease too long, e.g. 4^-3 years mean duration in this series. It is likely that with a subclinically vit D deficient diet parathormone effect on osteoid is varied. Absence of hypercalcaemia, renal and gastro-intestinal lesions are also indicative of lack of some additive factor to the excessive parathormone occurring in such instances of primary hyperparathyroidism in this geographic area.     

Bilateral choanal atresia in an adult: is it compatible with life?

Bilateral choanal atresia is potentially life-threatening. The condition almost always presents in the new born, with alternating phases of respiratory distress and apnoea relieved by crying. We report a rare case of bilateral choanal atresia presenting for the first time at 22 years of age. The patient had no features of cyanosis or apnoea, presenting only with bilateral nasal obstruction, rhinorrhoea and anosmia. His neonatal history was unremarkable. No syndromic association was noted excepting for telecanthus. The presence of bony atresia was confirmed on computed tomography (CT) scan and transnasal endoscopic surgery was used to obtain a patent airway. This case is a rare report of bilateral choanal atresia presenting for the first time in adult life.