A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas

Summary This phase II study evaluated the antitumor activity of the tetracycline analog COL-3, a potent inhibitor of metalloproteinases (MMPs), particularly MMP-2 and MMP-9, on a continuous oral schedule at a dose of 50 mg/m² daily in patients with advanced and/or metastatic soft tissue sarcoma (STS). The principal endpoints were the rate of objective tumor regression and the proportion of patients who did not experience disease progression during the first 8 weeks of treatment. Other study objectives included an assessment of pharmacology of COL-3, time to progression (TTP), and overall survival. A Simon two-stage design with multinomial stopping rule was employed, with 15 patients enrolled during the first stage of the study. Although COL-3 was generally well-tolerated, there were no objective responses and 5(33%) patients experienced disease progression during the first 8 weeks of treatment, which exceeded the criteria established a priori with regard to pursuing further evaluations of COL-3 in STS. The median values for TTP and survival were 109 and 279 days, respectively. Based on these results, further studies of COL-3 on this administration schedule in patients with STS are not warranted. An erratum to this article can be found at     

Marimastat: the clinical development of a matrix metalloproteinase inhibitor

Marimastat (BB-2516) is the first orally bioavailable matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed Phase I, II and some Phase III trials. In Phase I studies, which recruited patients with various malignancies, the main toxicity observed was mild to severe joint and muscle pain seen in > 60% of patients receiving a dose of marimastat > 50 mg b.i.d. The symptoms were reversible on discontinuation of the drug and their incidence has been reduced by using marimastat 10 mg b.i.d. In a number of Phase II studies in a variety of tumours, serum tumour markers were used as surrogate determinants of efficacy. Results were interpreted as indicating activity, but this has not yet translated into improved survival in the Phase III studies, which have been completed in pancreatic or gastric carcinoma and glioma. It is likely that these drugs will be most effective in the setting of minimal tumour volume such as in adjuvant treatment or maintenance therapy following response to standard cytotoxics. Therefore, the analysis of Phase III studies in small cell lung cancer (SCLC) where this hypothesis has been tested is awaited with interest. Marimastat can be safely co-administered with conventional cytotoxics and radiotherapy and Phase III studies using these approaches are currently ongoing.     

Marimastat: the clinical development of a matrix metalloproteinase inhibitor

Marimastat (BB-2516) is the first orally bioavailable matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed Phase I, II and some Phase III trials. In Phase I studies, which recruited patients with various malignancies, the main toxicity observed was mild to severe joint and muscle pain seen in > 60% of patients receiving a dose of marimastat > 50 mg b.i.d. The symptoms were reversible on discontinuation of the drug and their incidence has been reduced by using marimastat 10 mg b.i.d. In a number of Phase II studies in a variety of tumours, serum tumour markers were used as surrogate determinants of efficacy. Results were interpreted as indicating activity, but this has not yet translated into improved survival in the Phase III studies, which have been completed in pancreatic or gastric carcinoma and glioma. It is likely that these drugs will be most effective in the setting of minimal tumour volume such as in adjuvant treatment or maintenance therapy following response to standard cytotoxics. Therefore, the analysis of Phase III studies in small cell lung cancer (SCLC) where this hypothesis has been tested is awaited with interest. Marimastat can be safely co-administered with conventional cytotoxics and radiotherapy and Phase III studies using these approaches are currently ongoing.     

Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor,leading to the irregular absorption profile in rats after oral administration

Purpose. This study was undertaken to elucidate the underlying mechanism of the irregular absorption profiles of COL-3, a matrix metalloproteinase inhibitor, with a double- or plateau-peak concentration after a single oral dose administration of COL-3 suspension to rats. Methods. The gastrointestinal absorption profiles of COL-3 in rats were assessed by comparing serum drug concentration curves after the following various modes of drug administration: oral and intraduodenal doses, oral doses of COL-3 in fine and coarse suspensions, intraduodenal dosing to the bile-duct intact and cannulated (BDC) rats, and oral doses with and without food. In addition, the biliary excretion of COL-3 in the BDC rats was examined. Results. Neither variable gastric emptying nor enterohepatic recycling was the source of the irregular gastrointestinal absorption of COL-3 in rats. Reduction in particle size, presence of food and endogenous bile emerged as the determinants of the oral absorption of COL-3 by enhancing the dissolution of the solid drug in the gastrointestinal fluids. Flip-flop of the absorption and elimination rate constants was noted only for COL-3 after intraduodenal administration of the coarse suspension to the BDC rats with the bile flow diverged out of the body. Conclusions. Variability in dissolution rate-limited absorption was the main cause of the irregular absorption of COL-3 after oral administration of its solid dosage form.     

MMP-2、MMP-9及其抑制因子TIMP-1、TIMP-2在宫颈癌中的表达

目的分析基质金属蛋白酶2（MMP-2）和MMP-9及其抑制因子1（TIMP-1）和TIMP-2在宫颈癌不同位置中的表达情况及其临床意义。方法选取经病理证实的宫颈浸润癌患者118例（ICC组）、宫颈上皮内瘤样病变患者75例（CIN组）,取病变中心组织和边缘组织;选取正常官颈组织标本45例为对照组。采用SABC法行免疫组化检测各组中MMP-2、MMP-9、TIMP-1和TIMP-2因子表达阳性率、染色强度和表达强度。比较各组相关因子表达情况差异。结果ICC组中MMP-2和MMP-9的阳性率、染色强度和表达强度显著高于CIN组和对照组,TIMP-1和TIMP-2的阳性率、染色强度和表达强度显著低于CIN组和对照组（P〈0．05）。在ICC组,边缘癌组织的MMP-2与MMP-9的阳性率、染色强度和表达强度明显高于中心癌组织,而TIMP-1与TIMP-2的阳性率、染色强度和表达强度明显低于中心癌组织（P〈0．05）。结论MMP-2、MMP-9及其抑制因子TIMP-1、TIMP-2与宫颈癌的发生、发展密切相关,可能在宫颈癌的侵袭与转移中发挥着重要作用。     

Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers

OBJECTIVE: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. MATERIALS AND METHODS: 48 male volunteers received single oral doses ranging from 10 - 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 - 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. RESULTS: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0-infinity linearly increased up to 63,167 ng/ml and 311,960 ng x h/ml at the 800 mg dose level, respectively; tmax and t1/2 ranged from 2 - 3 hours and from 9.5 - 15.5 hours, respectively. High-fat diets reduced Cmax from 21,565 ng/ml to 14,095 ng/ml but did not alter AUC0-infinity. Hydroxylated metabolites were detected in plasma in concentrations less than 1% of S-3304. Less than 1% S-3304 was excreted in urine. The AUC of one dosing interval and Cmax did not change after multiple doses but t1/2 increased from 9.5 - 10.0 hours to 12.5 - 13.5 hours. The 6beta-hydroxycortisol/ cortisol ratio was not changed after multiple doses suggesting no effect on CYP3A4 activity. CONCLUSION: S-3304 demonstrated a good safety profile and good systemic exposure when administered orally up to 800 mg b.i.d. during 10 - 17 days. At the highest dose level of 800 mg b.i.d., it was free of rheumatoid arthritis-like symptoms.     

Population pharmacokinetics of oxaliplatin in patients with metastatic cancer

Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2 to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration-time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h-1 and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.     

Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer

Summary Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m².     

慢性心力衰竭患者血清基质金属蛋白酶的变化及其临床意义

目的 探讨慢性心力衰竭（CCF）患者血清基质金属蛋白酶-2、9（MMP-2、MMP-9）的变化及其临床意义。方法 测定60例CCF患者及50名正常对照者MMP-2、MMP-9水平、用超声心动仪测定两组患者心脏结构和功能指标,分析血清MMP-2、MMP．9与CCF的关系。结果 CCF患者血清MMP-2、MMP-9水平明显高于对照者（P〈0．05）;左室收缩末内径、左室舒张末内径、左室收缩末期容积和舒张末期容积随着CCF病情加重而增大（P〈0．05）,左心室射血分数随着CCF病情加重而降低（P〈0．05）。结论 MMP-2,MMP-9共同参与了CCF的发生、发展．可作为反映心室重塑和心功能恶化的有效指标。     

喉鳞状细胞癌中MMP-1和TIMP-1表达的临床病理学意义

目的探讨喉鳞状细胞癌（LSCC）组织中基质金属蛋白酶-1（MMP-1）和基质金属蛋白酶抑制因子-1（TIMP-1）蛋白和mRNA的表达及其临床病理学意义。方法分别应用免疫组织化学和RT-PCR方法 ,检测喉鳞状细胞癌组织中MMP-1和TIMP-1的蛋白及mRNA表达情况。结果 MMP-1在喉鳞状细胞癌组织和癌旁组织中的蛋白表达阳性率比较,差异有统计学意义（P﹤0.05）,且MMP-1 mRNA在喉鳞状细胞癌组织中的表达高于癌旁组织（P﹤0.05）;TIMP-1在喉鳞状细胞癌组织和癌旁组织中的蛋白表达阳性率,差异有统计学意义（P﹤0.05）且TIMP-1 mRNA在喉鳞状细胞癌组织中的表达低于癌旁组织（P﹤0.05）。结论 MMP-1和TIMP-1表达与喉鳞状细胞癌的发生发展﹑浸润及转移有关,检测癌组织中的MMP-1和TIMP-1的基因及蛋白表达情况,有助于判断喉鳞状细胞癌的转移、TNM分期及预后。     

Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer

Summary Aims: To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. Patients and Methods: Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m²). Results: Accumulation of [G-³H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (± SD) apparent oral clearance of MS-275 was 38.5 ± 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. Conclusions: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.     

Recent advances in studies on hydroxamates as matrix metalloproteinase inhibitors: a review

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc- containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. The inappropriate expression of these MMPs constitutes part of the pathogenic mechanism in several diseases, therefore they are subject to inhibition. They can be inhibited by endogenous proteinase inhibitors such as 2-macroglobulin or by the family of tissue inhibitors of metalloproteinases (TIMPs), which are glycoproteins of molecular weight 21-30 kDa, consisting of 184-194 amino acid residues. Recently, many different classes of synthetic inhibitors have been developed in which the hydroxamic acidbased class of compounds (hydroxamates) have been most widely studied, as their hydroxamic acid group (CONHOH) enables them to act as a bidentate ligand with the zinc ion present in MMPs, leading to much stronger interaction with the receptor as compared to any other class of inhibitors. The present review describes in detail the recent development on this class of MMP inihibitors. Compounds like 12,17e, f, g and h, 45j, 45k, 50f, 62a, 63a, and 63b have been reported to be highly promising for further development.     

血浆一氧化氮、一氧化氮合酶和基质金属蛋白酶9在子宫颈癌中的临床意义

目的 探讨血浆一氧化氮（NO）、一氧化氮合酶（NOS）和基质金属蛋白酶（MMP-9）水平在子宫颈癌中的变化及临床意义.方法 经病理活检确诊为宫颈癌患者69例,分别于手术前1d、术后15 d、30 d空腹抽取外周静脉血,健康对照组取空腹静脉血,采用化学比色法和ELISA法分别测定血浆中NO、NOS和MMP-9含量,比较上述指标的变化及相关性.结果 宫颈癌患者血浆中NO、NOS、MMP-9的水平与健康对照组相比明显增高.宫颈癌患者手术前与手术后15 d、30 d NO水平比较,手术后NO、NOS、MMP-9的水平均明显降低,但仍明显高于对照组.宫颈癌患者有淋巴结转移者NO、NOS、MMP-9水平明显高于无淋巴结转移者;相关性分析表明,血清中MMP-9与NO、NOS呈明显正相关性.结论 检测血浆中NO、NOS和MMP-9水平的变化,对宫颈癌的病情判断及临床治疗指导具有参考意义.     

Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m(2)/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m(2)/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.