Injection Of Vinblastine Research Articles

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Repair after traumatic injury often starts with mitotic activation around the lesion edges. Early midline cells in the Drosophila embryonic CNS can enter into division following the traumatic disruption of microtubules. We demonstrate that microtubule disruption activates non-canonical TNF signaling by phosphorylation of TGF-β activated kinase 1 (Tak1) and its target IkappaB kinase (Ik2), culminating in Dorsal/NfkappaB nuclear translocation and Jra/Jun expression. Tak1 and Ik2 are necessary for the damaged-induced divisions. Microtubule disruption caused by Tau accumulation is also reported in Alzheimer's disease (AD). Human Tau expression in Drosophila midline cells is sufficient to induce Tak1 phosphorylation, Dorsal and Jra/Jun expression, and entry into mitosis. Interestingly, activation of Tak1 and Tank binding kinase 1 (Tbk1), the human Ik2 ortholog, and NfkappaB upregulation are observed in AD brains.

Impact of Diamond Nanoparticles on the Efficiency of Vinblastine against Ehrlich Solid Carcinoma in Mice

Aim: This investigation pointed to estimate skeletal muscle efficiency of diamond nanoparticles in enhancing Vinblastine (VBL) effects. 
 Methodology: One hundred Albino mice, weighing (23- 28 grams) were utilized in this research, after a week of habituation, the mice were divided into five groups at random (20 mice each). Group 1 (control) obtained distilled water infusions, Group 2 (ESC group) injected Ehrlich cells via intramuscular infusion (IM), and Group 3 (ESC+VBL group) gained Vinblastine only, Group 4 (ESC+VBL+ND) received an IM injection of Vinblastine loaded on diamond nanoparticles and Group 5 (ESC+VBL+CS+ND) received IM administration of Vinblastine stacked on Chitosan with nanodiamond. Finally, blood specimens were taken. Serum was obtained to measure Asparaginase aminotransferase, Alanine aminotransferase, and Creatinine kinase. The muscle was removed and observed under a light microscope. 
 Results: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Creatinine kinase levels in the blood were elevated in ESC than in normal and treated groups. Levels of these enzymes were enhanced after treatment of VBL, diamond nanoparticles and chitosan. 
 Conclusion: Nanodiamond are influenced in the VBL delivery system for the therapy of Ehrlich Solid carcinoma in mice models. The embattled VBL liberates tumor cells and reduced the side effect of VBL on skeletal muscle.

Experimental model and approaches to investigation of the acquired resistance to tumor transplantation in mice

Introduction. An acquired resistance to experimental tumors was detected in animals that recovered from a primary transplanted tumor due to treatment or spontaneously, and demonstrated intolerance to a renewal tumor inoculation. This phenomenon is much less frequently observed, although it is of great scientific interest and medical significance. Here, we have addressed the expression of the resistance phenomenon in a model tumor in mice – Nemeth–Kelner lymphoma (NK/Ly). The aim of our study was to elaborate a reproducible method for induction of resistance to transplantation of lymphoma NK/Ly in mice and to investigate the mechanisms of its development. Methods and Results. Three schemes for induction of resistance were tested. The first one included treatment of tumor-bearing mice with vinblastine and, thereafter, reconvalescent animals were checked for the development of resistance expressed as a complete suppression of tumor growth after re-inoculation of tumor cells. Mice were inoculated intraperitoneally with NK/Ly ascitic cells and then subjected to 2–4 intraperitoneal injections of vinblastine at a dose of 1mg/g of body weight. The recovered mice were re-inoculated with tumor cells and the absence of tumor growth was considered as resistance development. The disadvantage of this approach is that less than 5% of mice achieve a long lasting recovery due to the treatment. The second scheme included the immunization of mice with intraperitoneal injection of the minimal number of viable tumor cells that do not cause tumor growth, but initiate the immune response. However, this approach was not effective, since there was no reliable number of cells correspon­ding to these demands. The minimal number of 15×103 injected cells per mouse caused a retarded but still progressive tumor growth. In the third scheme, the immunization of mice was conducted by the intraperitoneal injections of NK/Ly cells permeabilized with saponin. It should be noted that treatment with saponin leads to cell death with a minimal damage to cell morphology. The scheme of immunization with permeabilized NK/Ly cells appeared to be simple and effective. It provided a reproducible resistance to transplanted tumor and might be used as a model in studies of the mechanisms of this phenomenon. Cytological investigation of tumor and immunocompetent cells in ascites of control and of tumor-resistant mice was conducted. As revealed, the number of lymphocytes in ascites of tumor-resistant mice was about 4 times higher than such amount in the control (non-resistant) mice. A destruction of tumor cells by the adherent mono-nuclears was observed. Conclusions. The method of induction of resistance to transplantation of experimental tumor NK/Ly by immunization of mice with tumor cells permeabilized with saponin is described. The intraperitoneal inoculation of tumor cells to the tumor-resistant mice caused the marked increase of the mononuclear leukocytes population in the peritoneal fluid, which showed a harmful effect upon tumor cells. Thus, the induction of resistance to transplantation of NK/Ly lymphoma in mice might be provided mainly via the mechanisms of cell immunity, in particular, by the appearance of cytotoxic lymphocytes specific to distinct tumor cells.

Vinblastine-Loaded Nanoparticles with Enhanced Tumor-Targeting Efficiency and Decreasing Toxicity: Developed by One-Step Molecular Imprinting Process.

Molecularly imprinted polymers have exhibited good performance as carriers on drug loading and sustained release. In this paper, vinblastine (VBL)-loaded polymeric nanoparticles (VBL-NPs) were prepared by a one-step molecular imprinting process, avoiding the waste and incomplete removal of the template, and evaluated as targeting carriers for VBL delivery after modification. Using acryloyl amino acid comonomers and disulfide cross-linkers, VBL-NPs were synthesized and then conjugated with poly(ethylene glycol)-folate. The dynamic size of the obtained VBL-NPs-PEG-FA was 258.3 nm (PDI = 0.250), and the encapsulation efficiency was 45.82 ± 1.45%. The nanoparticles of VBL-NPs-PEG-FA were able to completely release VBL during 48 h under a mimic tumor intracellular condition (pH 4.5, 10 mM glutathione (GSH)), displaying significant redox responsiveness, whereas the release rates were much slower in the mimic body liquid (pH 7.4, 2 μM GSH) and tumor extracellular environment (pH 6.5, 2 μM GSH). Furthermore, the carriers NPs-PEG-FA, prepared without VBL, showed satisfactory intrinsic hemocompatibility, cellular compatibility, and tumor-targeting properties: they could rapidly and efficiently accumulate to folate receptor positive Hela cells and then internalized via receptor-mediated endocytosis, and the retention in tumor tissues could last for over 48 h. Interestingly, VBL-NPs-PEG-FA could evidently increase the accumulation of VBL in tumor tissues while decreasing the distribution of VBL in organs, exert similar anticancer efficacy against Hela tumors in the xenograft model of nude mice to VBL injection, and significantly improve the abnormality of liver and spleen observed in VBL injection. VBL-NPs-PEG-FA has the potential to be the delivery carrier for VBL by enhancing the tumor-targeting efficacy of VBL and decreasing toxicity to normal tissues.

Vinblastine, an anticancer drug, causes constipation and oxidative stress as well as others disruptions in intestinal tract in rat.

The purpose of this study is to examine the gastrointestinal disorders after injection of vinblastine (2mgkg-1b.w. i.v.) in rats. Animals were divided into two equal groups: Group 1 was considered as a control group (NaCl, 0.9%). Group 2 was treated with intravenous injection of vinblastine for 7days. Loperamide (2mgkg-1) was injected in a saline solution subcutaneously to induce constipation in another group of rats during the same period. Fecal parameters of the different groups have been determined. At the end of the experiment, animals were anaesthetized and sacrificed by decapitation. The intestinal mucosa specimens were examined for lipid peroxidation, sulfhydryl groups (-SH) and protein carbonylation as well as antioxidant enzyme activities and intracellular mediators. Gastrointestinal motility was realized by the test meal (10% charcoal in 5% gum arabic). In result, statistically significant decreases in the fecal number and water content collected during 24h were detected in the vinblastine group, but less important than loperamide control group. The animals treated with vinblastine, showed also a significant decrease (13%) of GIT, lower than that of loperamide (34%). The intestinal tissues from vinblastine-treated rats were showed a significant increase in lipoperoxydation and H2O2 production as well as a significant depletion of enzymatic and non-enzymatic antioxidants. Added to that, a disruption of intracellular iron and calcium levels was observed. Therefore, the present study provide the first strong evidence that vinblastine induced numerous disruptions in gastrointestinal which are related to oxidative stress and intracellular mediators disorders.

Molecularly imprinted nanoparticles and their releasing properties, bio-distribution as drug carriers

Molecular imprinted nanoparticles (MINPs) can memorize the shape and functional group positions complementary to template, which account for the large drug loading capacity and slow drug release behavior as drug carriers. We synthesized MINPs via precipitation polymerization with vinblastine (VBL) as a model drug, and investigated the drug loading, releasing property in vitro and bio-distribution in vivo. The obtained MINPs, from 300 to 450 nm, had smooth surface and favorable dispersibility. The entrapment efficacy and drug loading capacity of VBL loaded MINPs (MINPs-VBL) were 83.25% and 8.72% respectively. In PBS (pH7.4), MINPs-VBL showed sustained release behavior. The cumulative release percentage reached about 70% during 216 h and no burst release was observed. The releasing behavior of MINPs-VBL in vitro conformed to the first-order kinetics model. MINPs-VBL and commercially available vinblastine sulfate injection (VBL injection) were injected via tail vein of SD rats respectively to investigate the bio-distribution. MINPs-VBL group showed higher concentration of VBL in tissues and serum than VBL injection group after 60 min, and the drug level in liver was the highest. MINPs-VBL exhibited liver targeting trend to some extent, which was based on the evaluation of drug targeting index (DTI) and drug selecting index (DSI).

Gender difference in motor impairments induced by chronic administration of vinblastine.

Neurotoxicity of anticancer drugs complicates treatment of cancer patients. Vinblastine (VBL) is reported to induce motor and cognitive impairments in patients receiving chronic low-dose regimen. The effects of VBL treatment on motor, learning and memory functions of male and female Wistar rats were studied by behavioral related tests. Animals were given chronic intraperitoneal injections of VBL (0.2 mg/kg/week for 5 weeks) from postnatal day 23 to 52. Motor function was evaluated using grasping test and balancing was evaluated by the rotarod. Spatial learning and memory and anxiety-like behavior were determined using Morris water maze (MWM) task and open field test, respectively. Administration of VBL caused severe damage to motor and balance function of male rats in comparison to female rats treated with VBL and rats treated with saline. Memory and locomotion were affected in both male and female rats compared with saline treated rats, while a sex difference was also observed in these parameters; male rats showed more impairment compared with female ones. Both male and female rats showed cognitive impairments in MWM task and no sex differences were observed in these functions. Results revealed that VBL is a potent neurotoxic agent and despite the profound effect of VBL on motor and cognitive functions, it seems that male rats are more susceptible to motor deficits induced by VBL.

Relationship Between Cell Proliferation and Eruption Rate in the Rat Incisor

The aim of this study was to further define the relationship between cell proliferation and the rate of tooth eruption in the rat incisor. Vinblastine is a drug that blocks cellular mitosis and was used to inhibit cell proliferation in the odontogenic region of rat incisors that were submitted to a shortening treatment or to higher masticatory forces. Male Wistar rats were divided into five groups: normofunctional (control group for incisor eruption), hypofunctional (incisor submitted to eruption acceleration), hyperfunctional (incisors under higher masticatory forces), hypofunctional with vinblastine and hyperfunctional with vinblastine. In incisors submitted to shortening procedures, a significant decrease in the eruption rate and cell proliferation was observed two days after vinblastine injection, suggesting that incisor eruption is dependent on cell proliferation.

Respiration characteristics of mitochondria in parental and giant transformed cells of the murine Nemeth—Kellner lymphoma

Respiration characteristics of mitochondria of the parental and giant cells of murine NK/Ly (Nemeth-Kellner lymphoma) were studied. The giant cell-enriched ascites were obtained by serial intraperitoneal injections of vinblastine in tumour-bearing mice. Ascites containing >70% giant cells were used. Their diameter of was over 17 μm (~2800 μm(3)), while the diameter of the parental cells was 12.7 μm (1100 μm(3)). The respiration rate of mitochondria in situ was measured by oxygen consumption in intact and digitonin-permeabilized NK/Ly cells. Endogenous respiration of intact giant NK/Ly cells was three times higher compared to the parental ones, roughly in agreement with the volume change. The giant NK/Ly cells were far more resistant to permeabilization with digitonin than the parental cells, as shown by Trypan Blue and LDH (lactate dehydrogenase) release tests. After digitonin permeabilization, oxygen consumption was reduced to a minimal level (0.06 ng atom O/(s × 106 cells) in both types of cells. Addition of α-ketoglutarate or succinate to the incubation medium increased oxygen consumption in the parental cells by 46 and 164% respectively. In the giant NK/Ly cells, the corresponding increases were 164 and 276%. Addition of ADP to α-ketoglutarate- or succinate-supplemented medium further stimulated oxygen consumption of the permeabilized NK/Ly cells; however, the effect of ADP was more pronounced in the giant cells. In addition, indices of respiratory control were significantly higher in the giant cells. Oligomycin suppressed considerably the respiration of the intact giant cells but had a much weaker effect on parental cells. Thus, giant NK/Ly cells possess much higher respiration rates and show tighter coupling between the respiration and oxidative phosphorylation compared with parental cells.

Multisystem Langerhans Cell Histiocytosis in Children

Langerhans cell histiocytosis (LCH) is a rare (about 3-5 cases per million children aged 0-14 years), non-malignant disease characterized by proliferation and accumulation of clonal dendritic cells, extreme clinical heterogeneity, and an unpredictable course. Three large-scale, international, prospective therapeutic studies (LCH-I to III) for multisystem LCH (MS-LCH) have been conducted by the Histiocyte Society since 1991. The cumulative lessons from these studies are summarized in this review. Patients with MS-LCH represent a heterogeneous group with respect to disease severity and outcome, therefore treatment stratification and risk-tailored treatment are mandatory. The risk for mortality can be predicted based on involvement of 'risk organs' (e.g. hematopoietic system, liver, and/or spleen) at diagnosis and on response to initial therapy (assessed after 6-12 weeks of treatment). Thus, patients without involvement of risk organs (low-risk group) are not at risk for mortality but need systemic therapy in order to control the disease activity and avoid reactivations and permanent consequences. Patients with risk organ involvement (risk group) are at risk for mortality, and lack of therapy response defines a subgroup with a particularly dismal prognosis (high-risk group). Those patients in the risk group who respond to therapy and survive are at risk for reactivations and permanent consequences. The LCH-I study compared the efficacy of vinblastine and etoposide, and concluded that they are equivalent single-agent treatments for children with MS-LCH. However, the results of this trial were inferior with respect to response rate at week 6, disease reactivation rate, and sequelae, when compared with historical trials using more intensive regimens. The combination of prednisolone and vinblastine was established as a standard first-line treatment through the LCH-II and LCH-III studies. The regimen consists of one to two 6-week courses (continuous oral corticosteroids 40 mg/m2/day for 4 weeks, tapered over 2 weeks plus weekly vinblastine intravenous push) of initial therapy, followed by a continuation phase (three weekly pulses of oral prednisolone 40 mg/m2/day for 5 days plus a vinblastine injection). The addition of a third drug to the standard combination (etoposide in LCH-II and methotrexate in LCH-III) failed to significantly improve survival in the risk group. The remaining mortality in the risk group is about 20%, and up to 40% in the high-risk group. Concerning low-risk MS-LCH, comparison of results of the LCH-II study with historical data suggested that the remaining reactivation rate of about 50% (and possibly permanent consequences) could be reduced by prolongation of the total treatment duration. To study this hypothesis, in the low-risk group of the LCH-III study standard maintenance therapy was randomly given for a total treatment duration of 6 and 12 months. Unpublished preliminary data from this recently closed trial suggested that prolongation of the treatment duration may significantly improve reactivation-free survival. In summary, several studies have shown that systemic therapy is indicated for all patients with MS-LCH. A standard two-drug regimen consisting of an initial 'intensive' phase for 6-12 weeks, followed by a less intensive 'maintenance phase' for a total treatment duration of at least 12 months is recommended for patients treated outside of clinical trials. Non-responders, particularly those with progressive disease in risk organs, are eligible for experimental salvage approaches. Remaining questions will be addressed in the upcoming LCH-IV trial, which is in the process of intensive preparation.

Évaluation du traitement de la maladie de Kaposi par la vinblastine au Togo: étude de 23 cas

The aim of this study was to evaluate the efficacy of treatment of AIDS-related and non AIDS-related Kaposi's sarcoma (KS) using vinblastine (Velbé®). A retrospective study was conducted between January 1990 and December 2009 in the Department of Dermatology at the Lomé teaching hospital. The therapeutic protocol is the administration of 10 injections of vinblastine every 15 days. Evaluation was done at 10 weeks, 5 months, 11 months and 17 months. Twenty-three patients including 11 cases of non AIDS-related KS and 12 cases of AIDS-related KS were included in our study. The average age of patients was 39.3 ± 11.2 years. The sex-ratio (M/F) was 6:7. At ten weeks, partial remission was 26% and failure rate was 74%. Side effects as a result of the first five injections were dominated by anemia. At 5 months, complete remission was 17% including 3 cases of non AIDS-related KS, partial remission was 26% including 4 cases of non AIDS-related KS. Side effects of the last five injections were dominated by anemia and nervous toxicity. At 11 months, one patient was lost to follow-up and complete remission persisted in 13% of the patients. At 17 months, complete remission persisted in 9% of the patients against 4% of relapses. No long-term side effects were identified. Our study shows a poor efficacy of vinblastine in the treatment of AIDS-related and non AIDS-related KS and confirms the hematologic and nervous toxicity of this drug. The efficacy is better in the non AIDS-related KS than in the AIDS-related KS.

Vinblastine in Children and Adolescents With High-Risk Anaplastic Large-Cell Lymphoma: Results of the Randomized ALCL99-Vinblastine Trial

The impact of adding vinblastine to a 4-month chemotherapy regimen, based on the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster 90 protocol, in childhood high-risk anaplastic large-cell lymphoma (ALCL) was assessed. Children and adolescents with high-risk ALCL, defined by mediastinal, lung, liver, spleen, or skin involvement, were eligible for the trial. After a prephase and one chemotherapy course, patients were randomly assigned to receive either five further chemotherapy courses without vinblastine or the same regimen with one vinblastine injection (6 mg/m(2)) during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The primary end point was event-free survival (EFS), analyzed on the intent-to-treat population. Between November 1999 and June 2006, 110 patients were randomly assigned to receive vinblastine, and 107 were randomly assigned not to receive vinblastine. Median follow-up was 4.8 years. Patients in the vinblastine arm had a significantly reduced risk of events during the first year (hazard ratio [HR] = 0.31; 95% CI, 0.15 to 0.67; P = .002) followed by an increased risk thereafter (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). Consequently, EFS at 1 year differed significantly (91% in the vinblastine group v 74% in the no-vinblastine group), with no difference at 2 years (73% and 70%, respectively). Overall EFS curves did not differ significantly (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). Thirty-one percent of weekly doses of vinblastine were reduced as a result of hematologic toxicity, although vinblastine was discontinued for toxicity in only three patients. Adding vinblastine during induction and as maintenance for a total treatment duration of 1 year significantly delayed the occurrence of relapses but did not reduce the risk of failure.

Dual Therapeutic Efficacy of Vinblastine as a Unique Chemotherapeutic Agent Capable of Inducing Dendritic Cell Maturation

Our recent unbiased functional screen of 54 chemotherapeutic drugs unveiled striking heterogeneity in their effects on dendritic cells (DC). Most notably, vinblastine (VBL) was found to induce phenotypic and functional maturation of DCs in vitro. Here, we sought to determine whether VBL exhibits "dual" therapeutic efficacy in living animals by directly killing tumor cells and by boosting host immunity via DC maturation. Local injection of VBL in a low dose into the skin of C57BL/6 mice induced in situ maturation of epidermal Langerhans cells. When coinjected with a model antigen, ovalbumin (OVA), VBL enhanced OVA-specific cellular and humoral immune responses. When injected directly into the OVA cDNA-transduced E.G7 tumors, VBL augmented clonal expansion of OVA-reactive CD8 T cells and CTL activities. In B16 melanoma model, intratumor VBL injection induced apoptosis of melanoma cells, phenotypic maturation of tumor-infiltrating DCs, and significant CTL activities. Although complete clearance was never achieved, growth kinetic of B16 melanoma was markedly reduced in C57BL/6 mice by intratumor VBL injection. Importantly, the same treatment was far less efficacious in immunocompromised severe combined immunodeficient mice, indicating the requirement of intact host immunity. Our results introduce a new concept that VBL may be used to design "immunostimulatory" chemotherapy regimens.

The Impact of the Association of Vinblastine during Induction Chemotherapy and as Maintenance Treatment in Children and Adolescents with High-Risk Anaplastic Large Cell Lymphoma: Results of a Randomized Trial of the EICNHL Group

Purpose: To assess the impact of addition of vinblastine (VLB) to standard chemotherapy induction courses, based on the NHL-BFM90 protocol, and then weekly for a total duration of treatment of one year in children with high-risk anaplastic large cell lymphoma (ALCL).Design: The ALCL99-VLB trial is a randomized trial involving most European groups and the Japanese group. This ALCL99-VLB trial is part of the factorial design ALCL99 trial also aiming to assess efficacy and safety of two methotrexate doses and administration schedules (ALCL99-MTX trial already reported). Chemotherapy was based on the NHL-BFM90 protocol. All patients received a 5-day cytoreductive prephase followed by 6 induction courses given every 21 days. Children with high-risk ALCL, defined as disease with mediastinal, lung, liver or spleen involvement or biopsy proven skin disease, were randomized before the second induction course to receive either no vinblastine (No-VLB arm, reference arm) or one vinblastine injection (6 mg/m²) during the five latter induction courses and then weekly as maintenance treatment (VLB-arm). The duration of chemotherapy was 4 months in the No-VLB-arm and 1 year in the VLB-arm. We report here the results of the final analysis, performed after 3 interim analyses, with a 2-sided p-value equal to .0412 and 95.88% confidence intervals [95.88%CI]. The main end-point was the Event-Free survival (EFS). The main analysis was performed on the intent-to-treat population.Results: Overall 217 patients (93% ALK+) were recruited between 11/1999 and 05/2006 in the VLB-trial: 110 in the VLB-arm and 107 in the No-VLB-arm. A major violation of protocol treatment was observed in 4 VLB-patients and 1 No-VLB patient respectively. In the VLB-arm, 100 patients started VLB maintenance treatment; their median total treatment duration was 53 weeks (range, 21 to 87 weeks) and the median dose intensity during maintenance treatment was approximately 4.9 mg/m2/week. At the time of this final analysis, all patients had a least 2-year follow-up, with a median follow-up equal to 4.7 years. A total of 66 events were reported, including 65 relapses or progressions and 1 treatment-related death as first event. No second malignancy has been reported so far. Compared to No-VLB patients, VLB-patients had a significantly lower risk of event during the first year, Hazard Ratio of event, HR=0.31 [0.15 to 0.67], p=.002, whereas they had an increased risk of event after the first year, HR=5.0 [1.65 to 15.0], p=.003. Consequently, EFS rates differed greatly at 1 year (74% in the No-VLB-arm versus 91% in the VLB-arm) whereas they were very similar at 2 years (70% versus 74%). Over the whole follow-up period, the EFS curves did not differ significantly, HR=0.91 [0.55 to 1.51], p=.70. Results were very similar after exclusion of the 6 patients for whom the diagnosis of ALCL was rejected after review. There was no significant heterogeneity in the VLB-effect on the EFS between the two MTX groups (p=.85) or between the countries (p=.29). There was no significant impact of the addition of VLB on the complete remission rate (85% versus 86%, p=.82) or on the overall survival (p=.61, with 95% versus 92% at 2 years). Toxicity during induction courses was very similar in both arms. Only 3 patients stopped VLB maintenance treatment due to toxicity.Conclusion: The addition of vinblastine during induction and as maintenance treatment significantly delayed occurrence of relapses but, with this duration of treatment of 1 year, did not reduce the risk of failure resulting in the absence of benefit when considering the overall EFS curves or the 2-year EFS.

Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors

Preclinical studies indicate that conventional chemotherapeutic agents given continuously at low doses (metronomic chemotherapy) may provide an improved therapeutic index. Cyclophosphamide and vinblastine have been best studied in experimental models, where tumor growth inhibition is achieved, at least in part, through antiangiogenic mechanisms. Fifty patients with advanced solid tumors were enrolled in this phase II trial, 43 of whom had received at least one prior chemotherapy regimen. Patients were required to have Eastern Cooperative Oncology Group performance status of < or = 2, a life expectancy of >3 months, and at least one measurable lesion. All patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg) daily in addition to weekly injections of vinblastine (3 mg/m2). Half of the patients also received minocycline (100 mg) orally twice daily with the intent of further inhibiting tumor angiogenesis. The primary end point of the study was clinical benefit, defined as the percentage of patients experiencing an objective response or exhibiting stable disease for at least 6 months. For the 47 eligible patients, there were two (4%) complete responses and four (9%) partial responses, for an overall objective response rate of 13%. An additional eight patients achieved disease stabilization (stable disease > or = 6 months) (17%). The primary end point of clinical benefit was therefore 30%, (95% confidence interval, 16-44%). The median progression-free survival for all patients was 103 days and 289 days for patients experiencing clinical benefit. The incidence of patients experiencing grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0), and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea, vomiting, mucositis, or alopecia. This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population and indicate that this approach merits further investigation in specific disease site studies.

A teenager's experience of cancer

A teenager's experience of cancer

A phase II clinical trial involving the use of low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors

3137 Background: Preclinical studies indicate the conventional chemotherapeutic agents given continuously at low doses may provide an improved therapeutic index (RS Kerbel et al, Annals of Oncology 13:12–15, 2002). Cyclophosphamide and vinblastine have been best studied in experimental models where tumor growth retardation is achieved, at least in part, through antiangiogenic mechanisms. Methods: 50 with advanced solid tumors were enrolled (26 male and 24 female, median age 63 years - range 24 - 85). 43 patients had received at least one prior chemotherapy regimen. Patients were required to have ECOG performance status < 2, a life expectancy of > 3 months and at least one measurable lesion. All patients received cyclophosphamide 50 mg PO daily, weekly injections of vinblastine 3 mg/m2, and rofecoxib 25 mg PO daily. Results: Of the 45 evaluable patients, there were 2 complete responses (CR) (4%), 4 partial responses (PR) (9%) for an overall objective response rate of 13%. An additional 6 patients achieved disease stabilization (SD) ≥ 6 months (13%). The primary endpoint of clinical benefit (CR + PR + SD ≥ 6 months) was, therefore, 26%. The median progression-free survival for all patients was 105 days, and 240 days for patients experiencing clinical benefit. The incidence of grade 3/4 toxicities were as follows: neutropenia 12/2, anaemia 2/0, and thrombocytopenia 1/0. No patients developed grade 3 or 4 nausea, vomiting, mucositis or alopecia. Conclusions: This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population, and indicate that this regimen merits further investigation in specific disease site studies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This clinical research was supported only by the Northern Cancer Research Foundation - a non-profit, regional charitable organization. No personal income was included in this support.

Neutrophil depletion attenuates interleukin-8 production in mild-overstretch ventilated normal rabbit lung.

Acute lung injury induced by lung overstretch is associated with neutrophil influx, but the pathogenic role of neutrophils in overstretch-induced lung injury remains unclear. To assess the contribution of neutrophils, we compared the effects of noninjurious large tidal volume (Vt) ventilation on lungs in normal and neutrophil-depleted animals. Research animal laboratory. Twenty-six male Japanese white rabbits. Animals were mechanically ventilated for 4 hrs with one of the three following protocols: large Vt (20 mL/kg), small Vt (8 mL/kg), and large Vt (20 mL/kg) with neutrophil depletion achieved by a single dose of vinblastine injection (0.75 mg/kg) intravenously 4 days before the experiment. Large Vt ventilation produced alveolar neutrophil influx compared with low Vt (p =.002) without evidence of edema or increased epithelial permeability. The neutrophil influx was accompanied by increases in interleukin-8 in bronchoalveolar lavage fluid (p =.04). Immunohistochemistry of large Vt lungs showed increased interleukin-8 staining in bronchial epithelial cells, alveolar epithelium, alveolar macrophages, and smooth muscles of pulmonary vessels. Neutrophil depletion attenuated the interleukin-8 increase in the lung. Large Vt did not increase plasma interleukin-8 or tumor necrosis factor-alpha in plasma and bronchoalveolar lavage fluid. No expression of p-selectin or intercellular adhesion molecule-1 was observed. Cyclic overstretching of normal rabbit lungs with noninjurious large Vt produced neutrophil influx and interleukin-8 increase in bronchoalveolar lavage fluid. Production of pulmonary interleukin-8 by lung overstretch might require the interaction between resident lung cells and migrated neutrophils. This study suggests that large Vt ventilation potentiates the predisposed, subclinical lung injury, such as nosocomial pneumonia or aspiration of gastric contents.

Neoadjuvant chemotherapy and radiation for inoperable carcinoma of the maxillary antrum: a matched-control study.

A matched-control study comparing standard radiotherapy versus neoadjuvant chemotherapy and radiation was undertaken to clarify the effects of neoadjuvant systemic chemotherapy for locally advanced squamous cell carcinoma of the maxillary antrum. Thirty-four patients with inoperable maxillary cancer were treated with neoadjuvant chemotherapy and radiotherapy (Group II). Before starting radiotherapy, all patients in Group II received two or three cycles of neoadjuvant chemotherapy consisting of cisplatin and a 5-day continuous infusion of 5-fluorouracil with or without intravenous injection of vinblastine. Radiation doses ranged from 66 Gy to 75 Gy (median, 70 Gy). The response rate, patterns of failure, toxicity, and survival for Group II were compared with those for 34 stage-matched patients treated with radiation alone (Group I). Despite a higher response rate to neoadjuvant chemotherapy, the recurrence rate and patterns of treatment failure were not influenced by the addition of neoadjuvant chemotherapy. In most cases, neoadjuvant chemotherapy did not interfere with subsequent radiotherapy, and radiation-induced late complications occurred equally in both treatment groups. After a median follow-up of 48 months, there was no significant difference in 5-year actuarial survival or disease-free survival between the two treatment groups. Radiation alone for inoperable maxillary cancer was clearly suboptimal for improving local control and survival rate, but neoadjuvant chemotherapy in addition to standard radiotherapy failed to demonstrate any therapeutic advantage over radiation alone.

Vinblastine and 5-fluorouracil sensitivity of xenografts of four pancreatic ductal adenocarcinomas: is there a correlation with histological and cytological tumour differentiation?

In a search for nuclear parameters which may predict chemosensitivity of ductal adenocarcinoma of the pancreas, the growth of four xenografted pancreatic carcinomas in response to chemotherapeutic agents was correlated with histological and cytological features of tumour differentiation. Histologically, the tumours were classified according to their ability to form glands into poorly (PaTu-2, PaTu-3), moderately (Panc-1) and well differentiated (PaTu-39) ductal adenocarcinomas. Cytologically, similar segregation of tumours was possible using the 'nuclear form factor', which was one of four nuclear parameters analysed by image cytometry on Feulgen stained tumour imprints. Histological and cytological differentiation correlated closely with tumour growth. One week after a single intraperitoneal injection of either vinblastine or 5-fluorouracil, both drugs inhibited the growth of PaTu-2 and PaTu-3 significantly. The growth of Panc-1 was only affected by vinblastine, while neither drug had an effect on PaTu-39. The results suggest that the response of pancreatic ductal adenocarcinoma to chemotherapeutic drugs may be, to some extent, predicted by histological and cytological differentiation features. However, within these lines, each tumour may show a specific response pattern.