Sub-chronic administration of vincristine sulfate induces renal damage and apoptosis in rats via induction of oxidative stress and activation of Raf1-MEK1/2-Erk1/2 signal transduction / La administración subcrónica de sulfato de vincristina induce daño renal y apoptosis en ratas por inducción de estrés oxidativo y activación de la transducción de señales Raf1-MEK1/2-Erk1/2

SUMMARY: In spite of being one of the most powerful anti-cancer drug, the nephrotoxicity of Vincristine (VCR) is not well established in either animals or humans. Hence, this study evaluates the nephrotoxic effect of VCR in rats after sub-chronic long-term administration. Rats were divided into 2 groups (n=10/group) of either control and VCR treated rats (50 mg/kg). Treatments were carried out for 30 consecutive days, after which a series of biochemical and molecular experiments related to kidney function were evaluated. VCR administration significantly decreased the survival rate (69.8 %) and impaired renal function as evidenced by lowered creatinine (Cr) clearance (Ccr), high serum levels of urea and Cr, increased urinary protein levels and resulted in sever cortex pathological alterations, including glomerulus congestion and damage as well as vascular degenerations up to necrosis of both proximal and distal convoluted tubules. Mechanistically, VCR lowered renal antioxidant potential and ATP levels, enhanced lipid peroxidation and induced inflammation. In addition, VCR induced activation of Raf-1-MEK1/2-ERK1/2 signaling pathway leading to downregulation of Bcl2 and upregulation of P53, Bax, and cleaved caspase-3. In conclusion, these findings show a nephrotoxic effect of VCR sulfate in rats after sub-chronic administration and such effect was mediated by activation of ERK1/2 induced apoptosis.

RESUMEN: A pesar de ser uno de los medicamentos de mayor eficacia contra el cáncer, aún no se ha establecido la nefrotoxicidad de la vincristina (VCR) en animales y humanos. Por lo tanto, este estudio evalúa el efecto nefrotóxico de la VCR en ratas después de la administración subcrónica a largo plazo. Las ratas se dividieron en 2 grupos (n = 10 / grupo) de control y ratas tratadas con VCR (50 mg / kg). Los tratamientos se llevaron a cabo durante 30 días consecutivos, después de los cuales se evaluaron una serie de experimentos bioquímicos y moleculares relacionados con la función renal. La administración de VCR disminuyó significativamente la tasa de supervivencia (69,8 %), dificultó la función renal, lo que se observó además en los bajos niveles de creatinina (Cr) (Ccr), los niveles séricos elevados de urea y Cr, un nivel más alto de proteína urinaria, los que dieron lugar a alteraciones patológicas severas de la corteza, incluido el glomérulo congestión y daño, como también degeneraciones vasculares, incluyendo la necrosis de los túbulos contorneados proximales y distales. Mecánicamente, el VCR redujo el potencial antioxidante renal y los niveles de ATP, mejoró la peroxidación lipídica y la inflamación inducida. Además, la VCR indujo la activación de la vía de señalización Raf-1-MEK1 / 2-ERK1 / 2 que conduce a la regulación negativa de Bcl-2 y la regulación positiva de P53, Bax y la caspasa-3. En conclusión, estos hallazgos muestran un efecto nefrotóxico del sulfato de VCR en ratas después de la administración subcrónica. Dicho efecto fue mediado por la activación de la apoptosis inducida por ERK1 / 2.

Analgesic Effects of Dexmedetomidine in Vincristine-Evoked Painful Neuropathic Rats

Dexmedetomidine, which is a selective alpha2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 microg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 +/- 0.4, 9.1 +/- 1.9, 13.0 +/- 3.6, 16.6 +/- 2.4, and 24.4 +/- 1.6 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 +/- 4.2, 57.1 +/- 6.8, 34.3 +/- 5.7, 20.0 +/- 6.2, and 14.3 +/- 9.5 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).

Analgesic Effects of Dexmedetomidine in Vincristine-Evoked Painful Neuropathic Rats

Dexmedetomidine, which is a selective alpha2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 microg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 +/- 0.4, 9.1 +/- 1.9, 13.0 +/- 3.6, 16.6 +/- 2.4, and 24.4 +/- 1.6 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 +/- 4.2, 57.1 +/- 6.8, 34.3 +/- 5.7, 20.0 +/- 6.2, and 14.3 +/- 9.5 g at saline, 12.5, 25, 50, and 100 microg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).

Vincristine induced neurotoxicity: Study of 75 cases

Concern for side-effects of therapy related to treatment of childhood malignancies is becoming an increasingly important topic. In this study, we evaluated extent of vincristine [VCR] induced neurotoxicity in a group of children who underwent chemotherapy, with VCR being part of the regimen. In this investigation, for 75 children [54% boys, 46% girls], aged between 1 to 14 [mean 6.5 +/- 4.3] years, serial weekly neurological examinations were performed; of the 75, 70 had acute lymphoblastic leukemia and 5 Wilm's tumor. All patients were on a chemotherapy protocol of at least 4 consecutive VCR [1.5 mg/m[2]] injections. Decreased deep tendons reflexes were seen in the Achilles reflex in 78%, and the patellar reflex in 53% of patients. Muscle weakness was found in 70% of patients, being mild in 76% of them. Four percent of patients showed severe weakness. Petosis, jaw pain, hoarseness, abdominal pain and constipation were seen in 15%, 6%, 12%, 12% and 12% respectively. Paresthesia was observed in 32 of 52 patients, over 4 years old. No cases of foot drop, urinary retention or facial nerve palsy were seen in this patient group. Children on usual doses of vincristine regimen may have neuropathic side effects but most of these side effects are mild and not troublesome

Early results evaluating the efficacy and toxicity of adriamycin, vincristine and etoposide Ave in the management of childhood hodgkin's disease

This study aimed to evaluate efficacy and toxicity of adriamycin, vincristine and etoposide in the management of childhood Hodgkin's disease as a salvage and first line therapy as well as limiting the use of involved field radiotherapy to partial responders to avoid unnecessary complications of radiotherapy children. Thirty-six patients with Hodgkin's disease were included in this study, twenty- four had no previous treatment and twelve were previously treated with either C-MOPP or Chl-VPP [five of them had refractory disease and the remaining seven attained a complete remission but relapsed later]. All patients were treated with adriamycin 30 mg/m2, vincristine 1.4 mg/m2 and etoposide 100 mg/m2 D1 and D15 repeated every 28 days for six cycles. Partial responders [PR] were subjected to a field radiation treatment after three cycles of chemotherapy [20 Gy/ten treatments/two weeks]. At the end of the six cycles of chemotherapy, all patients were in a complete remission [CR]. All the previously untreated patients were in a complete remission after a median follow up of 15.5 months. The relapse free survival in previously treated patients was 58.3% after a median follow up of 14 months. The relapse free survival for the whole group was 86.7% after a median follow up of 15 months

Reproductive toxicity of vincristine in male rats.

Gross morphological and gravimetric changes were observed in the male reproductive system of sexually mature rats as well as rats in pubertal transition, given a continuous treatment of vincristine at dose levels of 10/20 and 5/10 micrograms respectively per day, for 15 days. The treatment resulted in a drastic regression of entire male reproductive system, suggesting that vincristine would cause male reproductive toxicity.

Alternância intensiva de drogas sem resistência cruzada presumível com methotrexate, adriamicina, ciclofosfamida, vincristina e fluorouracil (MACOM-F) no câncer da mama avançado locorregional / A

E apresentada uma nova estratégia de tratamento do câncer de mama avançado locorregional, fundamentada no uso de drogas sem resistência cruzada pressumível ou toxidade cumulativa, em 12 ciclos semanais. A finalidade foi a de obter citorreduçäo rápida, visando a operabilidade e tratamento das micrometástases. As drogas empregadas foram a ciclofosfamida 300 mg/m e adriamicina 50 mg/m nas semanas 1, 3, 5, 7, 9 e 11; methotrexate 100mg/m e, 24 horas após, resgate pelo leucovorin 15 mg/m de 6/6 horas, por oito vezes, nas semanas 2, 4, 6, 8, 10 e 12; fluouroracil 600 mg/m nas semanas 2, 6 e 10 e vincristina 1,4 mg/m (máximo 2 mg) nas semanas 4, 8 e 12 (MACOM-F). Neste estudo fase II foram incluidas 24 pacientes considerados avaliáveis e em bom estado geral (PS 0 e 2). Dessas 24 pacientes, 22 (91 porcento) obtiveram respostas positivas, sendo nove 937 porcento) resposta completa (RC), 13 (54 porcento) resposta parcial maior do que 50 porcento (RP) e duas (9 porcento) com doença estável (DE), reduçäo do tumor menor do que 50 porcento. A toxidade foi considerada aceitável e 18 foram submetidas a mastectomia radical. Decorridos 53 meses do ínicio do protocolo, das 18 operadas, sete recidivaram e cinco faleceram. Neste período de 34 semanas de seguimento médio, 59 porcento estäo vivas e 44 porcento sem evidência de doença. Os objetivos deste estudo foram: 1) testar o fundamento da teoria de Goldie-Coldman no tratamento de câncer de mama avançado locorregional; 2) verificar a eficácia e toxidade da administraçäo sequêncial intensiva das drogas mais ativas na atualidade para o câncer de mama; 3) determinar a açäo do MACOM-F, seguido de cirurgia, na qualidade e aumento do intervalo livre da doença (ILD) e sobrevida (SV) dessas doentes. O MACOM-F foi muito eficaz como tratamento neoadjuvante desses casos de câncer de mama avançado locorregional, podendo se tornar a primeira opçäo nessas circunstâncias. Todavia, é necessário maior número de doentes tratados para sua definitiva recomendaçäo.