Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells

Experimental painful peripheral neuropathies produced by the chemotherapeutic drugs, paclitaxel and vincristine, are produced by relatively low doses that do not cause axonal degeneration in peripheral nerve. Using quantitative immunolabeling with the PGP9.5 antibody, we have investigated whether these painful neuropathies might be associated with degeneration that is confined to the region of the sensory fiber's receptor terminals in the skin. Because complete and partial nerve transections are known to cause an increase in PGP9.5 in epidermal Langerhans cells (LCs), we also examined whether this effect occurs in chemotherapy-treated animals. At the time of peak pain severity, rats with paclitaxel- and vincristine-evoked painful peripheral neuropathies had a significant decrease (24% and 44%, respectively) in the number of intraepidermal nerve fibers (IENF) in the hind paw glabrous skin and an increase (217% and 121%, respectively) in the number of PGP9.5-positive LCs, relative to control. However, neither loss of IENF nor an increase in PGP9.5-positive LCs was found in rats with a painful peripheral neuropathy evoked by the anti-HIV agent, 2',3'-dideoxycytidine. We also confirmed that there is a decrease in IENF and an increase in PGP9.5-positive LCs in rats with neuropathic pain following a partial nerve injury (CCI model) and in rats with a complete sciatic nerve transection. Partial degeneration of the intraepidermal innervation suggests mechanisms that might produce chemotherapy-evoked neuropathic pain, and activation of cutaneous LCs suggests possible neuroimmune interactions that might also have a role.     

Loss of singing ability caused by vincristine

Two patients who received vincristine therapy for lymphoma suffered marked impairment of ability to sing as a consequence of neurotoxicity. Slow recovery occurred on drug withdrawal.     

Vincristine treatment in steroid-dependent nephrotic syndrome

Treatment of children with steroid-dependent nephrotic syndrome (SDNS) continues to be a challenge when relapses recur after treatment with cyclophosphamide and side effects or non-compliance make steroids and cyclosporin unsatisfactory. We treated 12 patients with intravenous vincristine for SDNS in a regime of 1–1.5 mg/m² weekly for 4 weeks then monthly for 4 months. Four of the 5 patients in relapse when commencing vincristine remitted within 2 doses. Comparing relapse frequency in the 12 months before and after vincristine, there was a reduction from 4 to 1.5 (p=0.004) relapses per year. Median sustained remission was 5 months, but 1 frequently relapsing patient remains in remission 4 years after vincristine. Vincristine was also successfully used in 1 or 2 doses at weekly intervals for subsequent relapses in 5 patients. Side effects were minimal in most cases. Abdominal pain occurred in 2 patients who commenced vincristine at 1.5 mg/m², but resolved when continued at 1 mg/m². We felt vincristine had a role in a subset of children with challenging SDNS administered as 1 mg/m² weekly for 4 weeks then 1.5 mg/m² monthly for 4 months. Vincristine allowed steroid- and cyclosporin-sparing, contributed to long-term remission in some patients, and was especially valuable in children with poor compliance with oral medication. Many patients expressed a preference for a few doses of vincristine rather than a standard course of oral prednisolone or cyclosporin.     

ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.     

Experimental investigations on a sequential combination chemotherapy protocol

Summary This paper deals with experimental investigations concerning the composition of a cytostatic three-drug-protocol in diploid Ehrlich-Ascites-Tumor (EAT) cells in vivo at a far advanced stage of the disease. Hydroxyurea (HU) and vincristine (VCR) were used in very low doses to induce a modification of the growth pattern of tumor cells alike partial synchronization. Adriamycin (ADM) was selected as cytocidal drug during DNA synthesis of the partially synchronized cells. It was found that the sequential combination of HU and VCR (first HU and 12h thereafter VCR) caused the greatest alteration of growth pattern compared with other combination protocols. A further statistically significant increase of the degree of synchrony was observed after a second VCR administration—22 h after HU. By means of this protocol the EAT was subdivided into two proliferating subpopulations, a diploid and a tetraploid one. the tetraploid population resulted from surviving cells being not able to perform cytokinesis correctly, so that polynuclear cells and cells with a large single nucleus containing tetraploid DNA values were created. With respect to therapy, the administration of ADM at the time of DNA synthesis of the partially synchronized cells resulted in a statistically significant prolongation of the mean survival time and in 30% of cures of the animals. The dosage of ADM was 2.6 mg/kg, i.e., a nonlethal dose (50% of the LD₁₀). Other combinations, i.e., simultaneous or reversed sequential combinations, did not show any therapeutic improvement compared to single drug therapy of ADM.the present time visiting professorship at the Medical Clinic of the University of CologneSupported by Deutsche Forschungsgemeinschaft     

Retinal changes induced by treatment with vincristine and vinblastine

The mitosis-inhibiting Vinca-alkaloids vincristine sulphate and vinblastine sulphate were injected into the vitreous body. This treatment resulted in ultrastructural changes in the retina within an hour. The retinal nerve cells showed a marked increase in the number of cell organelles, including the 100 Å filaments found in their perikarya. The microtubules disappeared and crystalloid structures appeared within an hour. The axons became distended by accumulated cell organelles, usually surrounding a crystalloid. The synaptic bodies, especially the presynaptic ones, often contained crystalloids, and showed a transient increase in the number of synaptic vesicles. The inner segments of the photoreceptor cells showed similar ultrastructural alterations, and, in addition, stacks of membranous structures. The outer segments decreased in length, and only rudiments of these structures remained one week after the intravitreal injection. The non-pigmented epithelial cells and the Müller's neuroglial cells also showed marked structural alterations.These ultrastructural changes are consistent with the biochemical and fluorescence microscopic observations that vincristine and vinblastine both inhibit the intracellular flow of cell constituents, as previously demonstrated to be the case with colchicine. It is proposed that the structural changes in the individual cells reflect the drug-induced imbalance between the inhibited intracellular transport and the continued formation of the cell constituents characteristic of the afflicted cell.This study was supported by grants from M. Bergwalls Stiftelse, W. and M. Lundgrens Stiftelse, H. Hiertas Stiftelse, Swedish Medical Research Council (B 72-12 X-2543-04 A) and the Swedish National Cancer Society (265 - B 70-02 X).     

长春新碱联合低剂量环磷酰胺治疗系统性红斑狼疮的临床观察

目的评价长春新碱（VCR）联合低剂量环磷酰胺（CTX）治疗系统性红斑狼疮（SLE）的疗效和安全性。方法本研究为两个中心、随机、单盲、对照的临床试验。符合纳入和排除标准的50例SLE患者随机分为VCR＋CTX组（VCR1mg,12-24h内予CTX200-400mg,每3周1次）及单用CTX组（600-800mg/3周）,疗程24周,分别观察基线、12周、24周时各项指标及不良反应的发生情况,共41例患者完成试验。结果随访12周、24周与基线时相比及随访第24周与第12周相比,两组的SLEDAI、Cr显著下降（P〈0.05）,两组间变化均无差异（P〉0.5）;与基线值相比,随访第12周,VCR＋CTX组较CTX组BUN显著下降、PLT显著升高（P〈0.05）,随访第24周时,两组BUN均较基线、12周时显著下降（P〈0.05）,但PLT变化不明显（P〉0.5）。安全性方面,两组的不良反应发生率无差异（P〉0.05）。结论 VCR联合低剂量CTX可以有效改善SLE患者的症状,降低疾病活动度、改善肾功。两者联合安全性好,与CTX组相比,不良反应并未增加。     

ITRACONAZOLE-ENHANCED VINCRISTINE NEUROTOXICITY IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA

A boy with acute lymphoblastic leukemia (ALL) experienced life-threatening vincristine neurotoxicity while simultaneously exposed to itraconazole. Five pediatric and six adult cases of itraconazole-enhanced vincristine toxicity have been reported, all with ALL. Upon cessation of the itraconazole, the patient's symptoms resolved, which is similar to the outcome of the previously reported cases: 10 of 11 patients had complete resolution of symptoms.     

Efficacy and Safety of First Line Vincristine with Doxorubicin,Bleomycin and Dacarbazine (ABOD) for Hodgkin’s Lymphoma: a Single Institute Experience

Background: ABVD (doxorubicin, bleomycin, vinblastine (Vb) and dacarbazine) is the standard regimen inHodgkin’s lymphoma (HL).Vincristine (O) is a mitotic spindle agent like Vb. We aimed to evaluate the efficacyand safety of O as a part of ABOD in HL. Materials and Methods: Patients who had ABOD were enrolled. StageI-II HL were evaluated for unfavorable risk factors according to NCCN. National Cancer Institute CommonToxicity Criteria was used for toxicity. Results: Seventy-nine HL patients in our center between 2003 and 2007were evaluated retrospectively. Median follow-up was 54 months. Most of the patients were male in their thirddecade. Median ABOD cycles were 6 (2-8). Primary refractory disease rate was 17.7% whereas it was 5.1% forearly relapse and 5.1% for late relapse disease. Response rates were as 82.3% for complete response, 11.4%for partial response, 5.1% for stable disease and 1.3% for progressive disease. Half of relapsed patients hadautologous stem cell transplantation. Estimated 5-year failure-free survival was 71% and significantly longerin early stage patients without risk factors, bulky disease or radiotherapy (RT) (p=0.05, p<0.0001, p=0.02;respectively). Estimated 5-year overall survival was 74% and significantly longer in those who had no RT(p=0.001). Dose modification rate was 5.1% and chemotherapy delay rate was 19%. There were no toxicityrelateddeaths. Conclusions: ABOD seems to be effective with managable toxicity in HL, even in those with poorprognostic factors.