lactoferrin and Kidney-Neoplasms

We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors.. Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following dose-escalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin.. Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses.. Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Cell Proliferation; Demography; Female; Humans; Kidney Neoplasms; Lactoferrin; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Tomography, X-Ray Computed

Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).. Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.. TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.. TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Kidney Neoplasms; Lactoferrin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Analysis

To study the role that interleukin-8 might play in the activation of polymorphonuclear neutrophils during interleukin-2 therapy and the relationship of these phenomena to interleukin-2 induced toxicity.. A cohort study with measurements before and after the administration of interleukin-2.. Medical oncology department of a large teaching hospital.. Fourteen patients with metastatic renal cell carcinoma and 10 with metastatic melanoma being treated in a phase 2 study of the sequential combination of interferon-gamma and interleukin-2.. Plasma levels of tumour necrosis factor-alpha, interleukins-6 and 8 and markers of neutrophil activation (neutrophil elastase and lactoferrin) were measured in patients receiving 5 daily injections of interferon-gamma (100 micrograms/m2/day) followed by 5 days of interleukin-2 (18 x 10(6) IU/m2/day).. Tumour necrosis factor-alpha rose from baseline levels of 32 (range, 12 to 56) to 343 (103 to 787) pg/ml 3 hours after interleukin-2 administration returning to baseline values 21 hours later. Interleukins-6 and -8 rose from baseline levels of 6 (5 to 10) and 75 (35 to 100) to 2151 (152 to 7259) and 1283 (490 to 2500) pg/ml, respectively, at 4 hours after interleukin-2 with both returning to baseline values by 24 hours. Peak levels of neutrophil elastase and lactoferrin, both markers of neutrophil activation, occurred 6 hours after interleukin-2 administration.. These data indicate that following administration of interleukin-2 tumour necrosis factor-alpha is released followed sequentially by rises in interleukins-6 and -8. It is hypothesised that these events result in activation of polymorphonuclear neutrophils. These activated neutrophils may play an important role in initiating endothelial cell damage leading to the haemodynamic toxicity and the capillary leak syndrome which is typically seen following the administration of interleukin-2.

Topics: Adult; Aged; Carcinoma, Renal Cell; Cohort Studies; Female; Humans; Infusions, Intravenous; Interferon-gamma; Interleukin-2; Interleukin-6; Interleukin-8; Kidney Neoplasms; Lactoferrin; Leukocyte Count; Leukocyte Elastase; Male; Melanoma; Middle Aged; Neutrophil Activation; Pancreatic Elastase; Tumor Necrosis Factor-alpha

By immunohistochemistry, lactoferrin (Lf) expression was retrospectively investigated in 40 formalin-fixed paraffin-embedded kidney samples, obtained at surgery from an equal number of patients. Histologically, 28 cases were clear cell carcinomas (CCC), 7 papillary carcinomas (PC) and 5 chromophobe carcinomas (CC). Ten specimens of unaffected renal parenchyma were utilized as tissue control. On 4-microm thick sections, the Lf immunoreactivity was revealed either by a rabbit polyclonal or mouse monoclonal anti-human Lf antisera; the quantification of Lf immunoreactivity was performed using an intensity-distribution (ID) score. A positive immunoreaction by both anti-Lf antibodies was found in 62.5% (25/40) of RCC, mainly evident and diffuse by monoclonal antiserum. The immunoreactivity was observed in the cytoplasmic boundary of neoplastic cells in CCC and PC, while in CC Lf showed a diffuse granular cytoplasmic localization. Moreover, significant differences in Lf ID score were found among CCC and non-CCC variants (P<0.00001), the former showed a lower score; no relationships between immunohistochemical data and the sex or age of patients, grade of RCC, stage of the disease or degree of terminal anemia were encountered. Normal unaffected tubular structures were positive for Lf; glomeruli were unstained. The reduced Lf immunoexpression in some CCC may be because of the down-regulation of Lf gene due to the frequent deletion of 3p regions reported in this RCC variant.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Carcinoma, Renal Cell; Female; Humans; Immunohistochemistry; Kidney Neoplasms; Lactoferrin; Male; Middle Aged; Retrospective Studies

This study was designed to examine whether lactoferrin, a glycoprotein contained in neutrophils which binds free iron, mediates the anemia associated with renal cell carcinoma. Preoperative hematocrit, urinalysis, serum iron, total iron binding capacity, and ferritin levels were obtained in 24 patients with hypernephroma. At the time of radical nephrectomy, a tumor specimen was obtained from all 24 patients and corresponding normal renal tissue was obtained from eight patients. Fifteen patients had low serum iron, whereas nine patients had normal serum iron. All tissue samples were snap frozen at the time of surgery and were subsequently sectioned into 3-microns slices using the cryostat. Then all the sectioned specimens were stained with FITC (fluorescein isothiocyanate) and peroxidase conjugated rabbit derived anti-human lactoferrin. Ten of the 15 patients with low serum iron had positive anti-lactoferrin staining in both the FITC and peroxidase systems. None of the tumors from patients with normal serum iron and none of the normal renal parenchyma exhibited positive anti-lactoferrin uptake. Stains for iron in the bone marrow of two patients with low serum iron showed increased iron stores. These studies suggest that lactoferrin mediates the anemia often seen in association with renal cell carcinoma.

Topics: Anemia; Bone Marrow; Carcinoma, Renal Cell; Humans; Immunoenzyme Techniques; Iron; Kidney Neoplasms; Lactoferrin; Lactoglobulins