奥沙利铂致大鼠周围神经系统毒性的病理学研究

目的:探讨奥沙利铂致大鼠周围神经系统毒性损害的病理改变是否具有时间依赖性与药物剂量依赖性的特点。方法:利用光镜和透射电镜技术观察大鼠后根神经节(dorsal root ganglia,DRG)及坐骨神经在奥沙利铂不同应用剂量及不同作用时间点的病理改变,并利用图像分析系统对DRG的形态改变进行分析。结果:DRG内感觉神经元的细胞体、细胞核及核仁均有不同程度固缩,用药后24~48 h最为显著,5周后基本恢复。细胞体与细胞核的面积与药物剂量成线性关系(r2=0.957,P=0.001;r2=0.983,P=0.000),核仁面积与药物剂量成非线性关系(r2=0.984)。坐骨神经在用药后24 h可见轻微的髓鞘变性,5周后明显好转。结论:奥沙利铂周围神经系统毒性损害的靶器官主要为DRG,并以DRG内感觉神经元的核仁改变最为显著,周围神经的损伤很可能为继发性损伤,以上病理改变具有可恢复性及药物剂量依赖性的特点。     

多西他赛联合顺铂和氟尿嘧啶治疗进展期胃癌48例临床分析

目的：观察多西他赛（docetaxel）联合顺铂（DDP）和氟尿嘧啶（5FU）方案（简称DCF方案）对进展期胃癌的近期疗效和毒副反应。方法：对经病理学或细胞学确诊的48例进展期胃癌患者，采用DCF方案化疗：多西他赛40mg／m^2，静脉滴入1h，d1、d8、d15;DDP20mg／m^2，静脉滴入，d1～d5；5-FU750mg／m^2用便携式微量输液泵持续静脉输注，d1～d^5；28d为1个周期，至少2个周期评价疗效。结果：48例完全缓解（CR）3例，部分缓解（PR）22例，无变化（NC）16倒，进展（PD）7例，总有效率（RR）为52．08％。其中初治组有效率为68．18％（15／22），有2例CR；复治组有效率为38．46％（10／26），有1例CR，两组差异有统计学意义，P=0．04。毒副反应主要为骨髓抑制、消化系统反应和脱发。大部分患者为Ⅰ、Ⅱ度反应，耐受良好。骨髓抑制为剂量限制性毒性，其中白细胞减少占64．58％，Ⅲ～Ⅳ度占16．67％。结论：多西他赛联合DDP和5-FU治疗进展期胃癌具有近期疗效好，毒副反应轻，耐受好的特点，且初治者疗效优于复治者，值得进一步研究推广。     

不同水化方案对乳癌患者顺铂肾毒性的影响

我们根据血浆和尿铂药代动力学与顺铂肾毒性关系的研究，提出了改良水化方案，并对３７例接受大剂量顺铂的乳癌患者，进行了两种不同水化方案的系统比较。结果表明，改良水化方案把原来输药后的利尿剂改为输药中，并增加了顺铂前１０００ｍｌ摄水量，使顺铂输注期间的尿量由平均８３７ｍｌ／３ｈ，增至２１８５ｍｌ／３ｈ，同时尿铂峰浓度从４７．３４μｇ／ｍｌ降至１３．４９μｇ／ｍｌ；并增加了夜间１２点肌注速尿一次，确保了夜间尿量不低于１００ｍｌ／ｈ，从而使肾毒性的发生率从７／１９（３６．８％）减少到１／１８（５．６％）。本研究证实了，改良水化方案通过降低尿铂峰浓度，能够进一步降低顺铂的肾毒性，且对其疗效无明显影响。     

多西他赛联合顺铂治疗晚期非小细胞肺癌48例临床分析

目的：观察多西他赛（docetaxel）联合顺铂（DDP）的治疗方案（简称DP方案）时晚期非小细胞肺癌（nonsmall cell lung cancer，NSCLC）的近期疗效和毒副反应。方法：对经病理学或细胞学确诊的48例晚期NSCLC患者，采用DP方案化疗：多西他赛35mg／m^2，静脉滴入1h，d1、d8；DDP75mg／m^2，静脉滴入，d1。21d为1个周期，至少2个周期评价疗效。结果：48例完全缓解（CR）3例，部分缓解（PR）22例，无变化（NC）16例，进展（PD）7例，总有效率（RR）为52．08％。其中初治组有效率为63．64％（14／22），有2例CR；复治组有效率为42．31％（11／26），有1例CR，两组差异有统计学意义，P=0．029。毒副反应主要为骨髓抑制、消化系统反应和脱发。大部分患者为Ⅰ、Ⅱ度反应，耐受良好。骨髓抑制为剂量限制性毒性，其中白细胞减少占64．58％，Ⅲ～Ⅳ度占16．15％。结论：多西他赛联合DDP治疗晚期NSCLC具有近期疗效好、毒副反应轻和耐受好的特点，且初治者疗效优于复治者，值得进一步研究推广。     

大剂量甲孕酮治疗复发转移乳癌

６２例复发转移乳癌患者接受口服大剂量甲孕酮治疗，５００ｍｇ／次，２～３次／天，３０天为一疗程。近期客观疗效：ＣＲ１．６％（１／６２），ＰＲ５３．２％（３３／３２），ＳＤ１７．７％（１１／６２），ＰＤ２７．４％（１７／６２）；骨转移、肺转移、胸壁软组织转移效果较好，胸腔积液、肝转移也有一定疗效。结果显示疗效与年龄有关，而与疗前一般状况积分（ＫＰＳ）、月经状况、既往激素治疗、术后无病生存期、复发转移部位数目、甲孕酮剂量无关；ＥＲ阳性患者有效率较ＥＲ阴性高，但统计学处理差异无显著性意义。口服大剂量甲孕酮治疗毒性反应较轻，主要是体重增加、出汗过多。     

盖诺联合顺铂治疗45例中晚期鼻咽癌临床观察

鼻咽癌对放射治疗敏感，放射治疗是其主要治疗方法。其恶性程度高，易发生局部复发和远处转移，5年生存率仍然较低。为进一步提高鼻咽癌的治疗水平，我们采用长春瑞滨（盖诺，NVB）与顺铂（DDP）联合治疗45例中晚期鼻咽癌，结果总结报道如下。     

钙镁合剂防治草酸铂神经毒性的临床研究

[目的]研究钙镁合剂防治草酸铂神经毒性的临床效果，为临床用药提供参考。[方法]62例采用草酸铂治疗的肿瘤患者，随机分为试验组（n=34）和对照组（n=28），试验组同时使用钙镁合剂。[结果]草酸铂导致了近90％的患者产生不同严重程度的神经毒性症状，而且神经毒性存在剂量效应关系．无神经毒性症状的病例全部集中在低、中累积剂量组；Ⅱ度及以上神经毒性症状病例全部集中在中、高累积剂量组（P〈0．001）。在加用钙镁合剂组患者中，轻度、急性的神经症状和持续时间长的Ⅱ～Ⅲ度毒性症状发生率与对照组相比均有明显降低（P〈0．05）。[结论]草酸铂具有特殊的神经毒性，钙镁合剂具有明显的预防草酸铂神经毒性症状效果。     

草酸铂与氟尿嘧啶及亚叶酸钙联合治疗晚期胃癌疗效观察

目的研究草酸铂（L-OHP）与氟尿嘧啶（5-Fu）及亚叶酸钙（CF）联合应用治疗晚期胃癌的疗效和毒副反应。方法采用L-OHI^3,100mg／m^2,静脉滴入2h,d1;CF200mg,静脉滴入2h,d1-5;5-Fu 500mg／m^2,静脉滴入6h,d1-5（CF滴完后）;21d为1周期。结果总有效率为37,5％,毒副反应以骨髓抑制、感觉神经毒性为主,白细胞下降发生率为53．1％,神经毒性发生率40．6％,无Ⅳ度毒剐反应。结论L-OHP、5-Fu、CF联合应用治疗晚期胃癌疗效肯定,毒副反应能耐受。     

吉西他滨与顺铂不同联合方案治疗非小细胞肺癌的临床观察

目的：观察吉西他滨与顺铂不同联合方案治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及毒副反应。方法：对经病理学或细胞学证实的62例晚期非小细胞肺癌患者给予吉西他滨与顺钩联合治疗，其中吉西他滨800-100mg／m^2，静脉滴入，d1、d8、d15；或d1、d8；顺铂25mg／m^2，d1-d3或d1、d8、d15；或d8-d10，静脉滴入。21d或28d为1个周期，每例患者治疗2个周期以上。结果：全组完全缓解1例，部分缓解28例，稳定25例，进展8例，总有效率46．8％。初治组28例有效率50％，复治组34例有效率41％。2组间比较有效率差异无显著性(P＞0．05)。各组骨髓毒性发生与文献中所报道的最低发生率资料相近，无严重毒副作用发生。未发生因血液毒性而导致的严重不良后果。Ⅲ-Ⅳ白细胞减少和血小板减少发生率分别为1．6％和8％，顺铂不同方法给药并未降低血液学方面的毒性，其余毒性反应均轻微，可以耐受。结论：吉西他滨与顺铂不同联合方案一线或二线治疗晚期非小细胞肺癌均有较好的疗效，毒性可以耐受。     

低浓度氢氧化钠、盐酸和无水酒精肝内注射对肝组织作用的动物实验研究

目的本研究观察低浓度氢氧化钠溶液、盐酸溶液肝内注射所产生的作用范围的大小、可控性和坏死程度的彻底性，并和无水酒精作比较，评价其替代无水酒精作为肝癌瘤内注射制剂的应用前景。方法新西兰兔45只，随机分为A、B、C、D、E五个组，每组9只。A组为5．0％氢氧化钠组，B组为2．5％氢氧化钠组，C组为5．0％盐酸组，D组为2．5％盐酸组，E组为无水酒精组。再根据注射剂量将每组9只随机分配到a、b、c三个亚组，每亚组3只。a亚组为0．5ml，b亚组为1．0ml，c亚组为1．5ml。每只动物肝脏内只进行一次药液注射。结果按病理结果是否完全坏死，作用范围是否局限，注射时是否溢出损伤肝包膜及腹腔脏器，肝、肾功能有无改变，超声是否能监控注射时的作用范围五个方面来评分，每个方面2分，总计10分。A组三个剂量每只兔子平均得分8．4（76／9），B组三个剂量平均得分8．7（78／9），明显高于C组3．O（27／9）和D组3．6（32／9）。无水酒精对照组平均每只兔子得分5．4（49／9）。结论5．0％和2．5％的氢氧化钠溶液肝内注射所产生的肝组织坏死，比盐酸和无水酒精更为彻底，范围也更局限，可能成为理想的瘤内注射制剂。     

Oxaliplatin causes selective atrophy of a subpopulation of dorsal root ganglion neurons without inducing cell loss

Peripheral neuropathy is induced by multiple doses of oxaliplatin and interferes with the clinical utility of the drug in patients with colorectal cancer. In this study, we sought to determine whether cell loss or selective neuronal damage was the basis for the peripheral neuropathy caused by oxaliplatin. Adult female rats were given 1.85 mg/kg oxaliplatin twice per week for 8 weeks. Nerve conduction and L5 dorsal root ganglia (DRG) were studied 1 week after the completion of all treatment. No mortality occurred during oxaliplatin treatment, but the rate of body weight gain was reduced compared to age-matched vehicle-treated controls. Oxaliplatin slowed conduction velocity and delayed conduction times in peripheral sensory nerves, without affecting central or motor nerve conduction. In L5 DRG, total numbers of neurons were unchanged by oxaliplatin, but there were significant reductions in neuronal size distribution, ganglion volume, average cell size and the relative frequency of large cells. In addition, the relative frequency of small DRG cells was increased by oxaliplatin. Oxaliplatin significantly altered the size distribution and average cell body area of the predominantly large parvalbumin-immunoreactive DRG neurons without affecting the frequency of parvalbumin staining. On the contrary, neither the staining frequency nor the size distribution of the predominantly small substance P-immunoreactive DRG neurons was changed by oxaliplatin. In conclusion, oxaliplatin causes selective atrophy of a subpopulation of DRG neurons with predominantly large parvalbumin-expressing cells without inducing neuronal loss. Because DRG cell body size and axonal conduction velocity are positively correlated, neuronal atrophy may be the morphological basis for the development of decreased sensory nerve conduction velocity that characterizes oxaliplatin-induced peripheral neuropathy.     

Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat

The aim of this study was to determine the influence of oxaliplatin scheduling on the onset of peripheral neurotoxicity and ototoxicity in a rat model. Animals were treated with four different schedules of oxaliplatin using two cumulative doses (36 and 48 mg/kg intraperitoneally (i.p.)). The neuropathological examination evidenced dorsal root ganglia (DRG) nucleolar, nuclear and somatic size reduction with nucleolar segregation in the treated rats. Sensory nerve conduction velocity (SNCV) was reduced after oxaliplatin treatment, while the auditory pathway was unaffected. After treatment, platinum was detected in the kidney, DRG and sciatic nerve. After a 5-week follow-up period, recovery of the pathological changes in the DRG and sciatic nerves occurred, although platinum was still detectable in these tissues. The following conclusions may be drawn: the main targets of oxaliplatin neurotoxicity were the DRG; the shorter the interval between the injections, the higher the severity of peripheral neuropathy and this was also related to the cumulative oxaliplatin dose; the peripheral neurotoxicity tended to be reversible; ototoxicity was absent even with high cumulative doses of oxaliplatin.     

Nucleolar damage correlates with neurotoxicity induced by different platinum drugs.

Platinum-based drugs are very useful in cancer therapy but are associated with neurotoxicity in the clinic. To investigate the mechanism of neurotoxicity, dorsal root ganglia of rats treated with various platinum drugs were studied. Cell body, nuclear and nucleolar dimensions of dorsal root ganglia sensory nerve cells were measured to determine morphological toxicity. Sensory nerve conduction velocity was measured to determine functional toxicity. After a single dose of oxaliplatin (10 mg kg(-1)), no significant change in nuclear and cell body diameter was seen but decreased nucleolar size was apparent within a few hours of treatment. Changes in nucleolar size were maximal at 24 hours, recovered very slowly and showed a non-linear dependence on oxaliplatin dose (r(2)= 0.99). Functional toxicity was delayed in onset until 14 days after a single dose of oxaliplatin but eventually recovered 3 months after treatment. Multiple doses of cisplatin, carboplatin, oxaliplatin, R, R-ormaplatin and S, S-ormaplatin were also associated with time-dependent reduction in nucleolar size. A linear correlation was obtained between the rate of change in nucleolar size during multiple dose treatment with the series of platinum drugs and the time taken for the development of altered sensory nerve conduction velocity (r(2)= 0.86;P< 0.024). Damage to the nucleolus of ganglionic sensory neurons is therefore linked to the neurotoxicity of platinum-based drugs, possibly through mechanisms resulting in the inhibition of rRNA synthesis.     

Paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons in vivo reducing oxaliplatin toxicity

Paclitaxel and oxaliplatin are promising drugs for combination trials but both induce peripheral neurotoxicity. To investigate this toxicity, 10-week-old female Wistar rats were given single intraperitoneal doses of paclitaxel and oxaliplatin, alone or in combination. Neurotoxicity was assessed by L5 dorsal root ganglion morphometry and H-reflex-related sensory nerve conduction velocity. Platinum concentrations in dorsal root ganglia and plasma were measured by inductively coupled plasma mass spectrometry. Dorsal root ganglion nucleolus size was significantly increased following single doses of paclitaxel of 10 and 20 mg kg(-1) at 24 h and 6 days (P<0.02). In contrast, dorsal root ganglion nucleolus size was significantly decreased following single doses of oxaliplatin ranging from 3 to 30 mg kg(-1) at time points ranging from 2 h to 14 days. Sensory nerve conduction velocity was altered after a single dose of oxaliplatin but not after paclitaxel. In combination with oxaliplatin, paclitaxel did not alter the plasma pharmacokinetics or dorsal root ganglion accumulation of oxaliplatin-derived platinum. However, prior paclitaxel inhibited oxaliplatin-induced reductions of dorsal root ganglion nucleolar diameter (P<0.02). Sensory nerve conduction velocity was reduced after oxaliplatin alone (P&<0.05) but unchanged when paclitaxel was given before oxaliplatin. In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.     

Neuroprotective interactions in rats between paclitaxel and cisplatin

Paclitaxel and cisplatin are associated with dose-limiting neurotoxicity that may result from their differing effects on microtubule stability in peripheral nerves. We hypothesized that such different actions of paclitaxel and cisplatin could be exploited to minimize their neurotoxicity by giving them in combination. Paclitaxel (9-18 micromol/kg/week or 7.7-15.4 mg/kg/week) and cisplatin (5-10 micromol/kg/week or 1.5-3 mg/kg/week) were given alone and in combination to female Wistar rats. Treatment was given once per week for a total of 7-10 weeks. Paclitaxel and cisplatin were given 24 h apart when they were given in combination. Changes in sensory nerve conduction velocity (SNCV) and dorsal root ganglia (DRG) morphology were measured. The nature of their interaction was analyzed using an isobologram. Their antitumor activity alone or in combination was also determined in C57B1/6 mice bearing colon 38 tumors. Reductions in SNCV occurred with paclitaxel alone (P = 0.009), cisplatin alone (P = 0.012), and cisplatin given 24 h before paclitaxel (P < 0.0001). In contrast, there was no significant change in SNCV with paclitaxel given 24 h before cisplatin (P = 0.11). An isobologram showed that the SNCV effects of the drug combinations were less than additive or antagonistic. Cisplatin-induced morphometric changes in DRG neurons were less marked when cisplatin was given with paclitaxel (P = 0.004). Concentrations of platinum in dorsal root ganglia, sural nerves, and sciatic nerves were not altered by giving paclitaxel before cisplatin. Tumor growth delays (TGD) were greater after treatment with paclitaxel (23.4 micromol/kg or 20 mg/kg) given 24 h before cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 7.5 days) than after paclitaxel (23.4 micromol/kg or 20 mg/kg) (TGD = 2.0 days) or cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 3.5 days) alone. Paclitaxel and cisplatin antagonized each other's neurotoxicity in Wistar rats. Combining cytotoxic agents with opposing effects on peripheral nerves has potential for minimizing neurotoxicity in patients.     

Oxaliplatin neurotoxicity

Oxaliplatin is a reference drug in the treatment of digestive-tract tumors, especially colorectal cancer. Its toxicity profile is dominated by a peripheral sensitive neuropathy, with neuromuscular manifestations. This neurotoxicity has 2 components: an acute toxicity characterized by a rapid onset of cold-induced distal dysesthesia and/or paresthesia, muscular contractions, numbness, stiffness, usually transient but able to evolve into a chronic, persistent sensory peripheral neuropathy that eventually causes functional impairment. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. This neurotoxicity is frequent, 80%of the patients and becomes chronic in 15 to 20%of the patients, sometimes irreversible. The mechanism of this neurotoxicity has been elucidated: an increased neuronal excitability is due to the action of oxaliplatin on voltage-gated sodium channels through chelation of calcium by the oxaliplatin metabolite. The prevention of this neurotoxicity is a major goal, taking in account the wide indications of this drug. Different approaches have been or are evaluated, based on pathogenic or practical concepts: 1) modifications of the administration schedule; 2) substances acting upon sodium channels : calcium-magnesium, carbamazepine, gabapentine, venlafaxin; 3) detoxifying agents and antioxydants: glutathion, amifostine, alphalipoic acid, tocopherol ; 4) substances used in other kinds of neuropathy: glutamine, alphalipoic acid; 5) neurotrophic factors: NGF, LIF; 6) oxaliplatin analogs, with a DACH platin, without oxalate. Calcium-magnesium infusion seem to be an efficient and safe approach. Further studies are necessary for a better understanding and prevention of this neurotoxicity, potentially severe.     

替吉奥联合奥沙利铂治疗晚期食管癌近期疗效观察

目的 观察替吉奥联合奥沙利铂治疗晚期食管癌的近期疗效及不良反应.方法 30例晚期食管癌均接受化疗,替吉奥80mg/(m2 ·d),分2次,餐后口服,dl-14;奥沙利铂130 mg/m2,dl,静脉滴注＞3小时,21天为1周期,2周期后行胸腹部CT及消化道钡餐造影或胃镜评价疗效,并评价不良反应.结果 30例患者均可评价疗效,完全缓解(CR)0例,部分缓解(PR) 12例,病情稳定(SD)8例,病情进展(PD) 10例,有效率(CR+ PR)为40.0％,临床获益率(CR+PR+SD)为66.7％.中位疾病进展时间5月,1年生存率63.3％.主要不良反应为血液学毒性、消化道反应、肝功能损伤、皮疹、神经毒性等.结论 替吉奥联合奥沙利铂治疗晚期食管癌疗效较好,不良反应可耐受.     

Neuronal expression of copper transporter 1 in rat dorsal root ganglia: association with platinum neurotoxicity

Purpose  We report the neuronal expression of copper transporter 1 (CTR1) in rat dorsal root ganglia (DRG) and its association with the neurotoxicity of platinum-based drugs. Methods  CTR1 expression was studied by immunohistochemistry and RT-PCR. The toxicity of platinum drugs to CTR1-positive and CTR1-negative neurons was compared in DRG from animals treated with maximum tolerated doses of oxaliplatin (1.85 mg/kg), cisplatin (1 mg/kg) or carboplatin (8 mg/kg) twice weekly for 8 weeks. Results  Abundant CTR1 mRNA was detected in DRG tissue. CTR1 immunoreactivity was associated with plasma membranes and cytoplasmic vesicular structures of a subpopulation (13.6 ± 3.1%) of mainly large-sized (mean cell body area, 1,787 ± 127 μm²) DRG neurons. After treatment with platinum drugs, the cell bodies of these CTR1-positive neurons became atrophied, with oxaliplatin causing the greatest percentage reduction in the mean cell body area relative to controls (42%; P < 0.05), followed by cisplatin (18%; P < 0.05) and carboplatin causing the least reduction (3.2%; P = NS). CTR1-negative neurons, with no immunoreactivity or only diffuse cytoplasmic staining, showed less treatment-induced cell body atrophy than CTR1-positive neurons. Conclusions  CTR1 is preferentially expressed by a subset of DRG neurons that are particularly vulnerable to the toxicity of platinum drugs. These findings, together with its neuronal membrane localization, are suggestive of CTR1-related mechanisms of platinum drug neuronal uptake and neurotoxicity.     

Comparative neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products utilizing a rat dorsal root ganglia in vitro explant culture model

Purpose: Neurotoxicity is one of the major toxicities of platinum-based anticancer drugs, especially oxaliplatin and ormaplatin. It has been postulated that biotransformation products are likely to be responsible for the toxicity of platinum drugs. In our preceding pharmacokinetic study, both oxaliplatin and ormaplatin were observed to produce the same types of major plasma biotransformation products. However, while the plasma concentration of ormaplatin was much lower than that of oxaliplatin at an equimolar dose, one of their common biotransformation products, Pt(dach)Cl₂, was present at 29-fold higher concentrations in the plasma following the i.v. injection of ormaplatin than of oxaliplatin. Because ormaplatin has severe neurotoxicity and Pt(dach)Cl₂ is very cytotoxic, we have postulated that Pt(dach)Cl₂ is likely to be responsible for the differences in neurotoxicity between ormaplatin and oxaliplatin. In order to test this hypothesis, we compared the neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products. Since the dorsal root ganglia (DRGs) have been suggested to be the likely targtet for platinum drugs and in vitro DRG explant cultures have been suggested to be a valid model for studying cisplatin-associated neurotoxicity, our comparative neurotoxicity study was conducted with DRG explant cultures in vitro. Methods: Based on the previous studies of cisplatin neurotoxicity, we established our in vitro DRG explant culture utilizing DRGs dissected from E-19 embryonic rats. Rat DRGs were incubated for 30 min with different platinum compounds to mimic in vivo exposure conditions; this was by followed by a 48-h incubation in culture medium at 37 °C. At the end of the incubation, the neurites were fixed and stained with toluidine blue, and neurite outgrowth was quantitated by phase-contrast microscopy. The inhibition of neurite outgrowth by platinum compounds was used as an indicator of in vitro neurotoxicity. Since an in vivo study has indicated that the order of neurotoxicity is ormaplatin > cisplatin ≥ oxaliplatin > carboplatin as measured by morphometric changes to rat DRGs, we initially validated our DRG explant culture model by comparing the in vitro neurotoxicity of ormaplatin, cisplatin, oxaliplatin, and carboplatin. After observing the same neurotoxicity rank between this study and a previous in vivo study, we further compared the neurotoxicity of oxaliplatin, ormaplatin, and their biotransformation products including Pt(dach)Cl₂, Pt(dach)(H₂O)Cl, Pt(dach)(H₂O)₂, Pt(dach)(Met), and Pt(dach)(GSH) utilizing the DRG explant culture model. Results: Our study indicated that Pt(dach)Cl₂ and its hydrolysis products were more potent at inhibiting neurite outgrowth than the parent drugs oxaliplatin and ormaplatin. In contrast, no detectable inhibition of neurite outgrowth was observed for DRGs dosed with Pt(dach)(Met) and Pt(dach)(GSH). Conclusion: This study suggests that biotransformation products such as Pt(dach)Cl₂ and its hydrolysis products are more neurotoxic than the parent drugs oxaliplatin and ormaplatin. The different neurotoxicity profiles of oxaliplatin and ormaplatin are more likely due to the different plasma concentrations of their common biotransformation product Pt(dach)Cl₂ than to differences in their intrinsic neurotoxicity. Received: 12 June 1998 / Accepted: 22 October 1998