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Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats.

Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, Nishiyama N, Kataoka K, Naito S, Kakizoe T - Br. J. Cancer (2005)

Bottom Line: In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP.On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004.These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

ABSTRACT
In spite of the clinical usefulness of cisplatin (CDDP), there are many occasions in which it is difficult to continue the administration of CDDP due to its nephrotoxicity and neurotoxicity. We examined the incorporation of CDDP into polymeric micelles to see if this allowed the resolution of these disadvantages. Cisplatin was incorporated into polymeric micelles through the polymer-metal complex formation between polyethylene glycol poly(glutamic acid) block copolymers and CDDP (NC-6004). The pharmacokinetics, pharmacodynamics, and toxicity studies of CDDP and NC-6004 were conducted in rats or mice. The particle size of NC-6004 was approximately 30 nm, with a narrow size distribution. In rats, the area under the curve and total body clearance values for NC-6004 were 65-fold and one-nineteenth the values for CDDP (P<0.001 and 0.01, respectively). In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP. Histopathological and biochemical studies revealed that NC-6004 significantly inhibited the nephrotoxicity of CDDP. On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004. Furthermore, rats given CDDP showed a significant delay (P<0.05) in sensory nerve conduction velocity in their hind paws as compared with rats given NC-6004. Electron microscopy in rats given CDDP indicated the degeneration of the sciatic nerve, but these findings were not seen in rats given NC-6004. These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (P<0.05). NC-6004 preserved the antitumour activity of CDDP and reduced its nephrotoxicity and neurotoxicity, which would therefore seem to suggest that NC-6004 could allow the long-term administration of CDDP where caution against hepatic dysfunction must be exercised.

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Neurotoxicity of CDDP and NC-6004 in rats. Rats (n=5) were given CDDP (2 mg kg−1), NC-6004 (an equivalent dose of 2 mg kg−1 CDDP), or 5% glucose, all i.v. twice a week, 11 administrations in total. (A) Sensory nerve conduction velocity and MNCV of the sciatic nerve at week 6 after the initial administration (control (), CDDP (•), and NC-6004 (□)). Histopathological changes of the sciatic nerve were examined by electron microscopy after the administration of CDDP (B) and NC-6004 (C). In rats given CDDP, widespread degenerations as indicated by loss of microtubules, loss of filaments, degeneration in the cytoplasm of Schwann cells (), and an irregular inner loop () were seen. On the other hand, animals given NC-6004 exhibited nearly normal electron micrographs of the sciatic nerve as the control animals. (D) Changes in relative body weight. Data were derived from the same rats as those used in the present study (control (×), CDDP (•), and NC-6004 (○)). (E) The Pt concentration in the sciatic nerve. Rats were given CDDP (▪) (5 mg kg−1, n=5), NC-6004 (□) (an equivalent dose of 5 mg kg−1 CDDP, n=5), or 5% glucose (n=2), all i.v. twice a week, four administrations in total. On day 3 after the final administration, a segment of the sciatic nerve was removed and the Pt concentration in the sciatic nerve was measured by ICP-MS. Body weight changes are expressed as the mean±s.e. The other data are expressed as the mean±s.d. *P<0.05, **P<0.001, NS: not significant.
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fig5: Neurotoxicity of CDDP and NC-6004 in rats. Rats (n=5) were given CDDP (2 mg kg−1), NC-6004 (an equivalent dose of 2 mg kg−1 CDDP), or 5% glucose, all i.v. twice a week, 11 administrations in total. (A) Sensory nerve conduction velocity and MNCV of the sciatic nerve at week 6 after the initial administration (control (), CDDP (•), and NC-6004 (□)). Histopathological changes of the sciatic nerve were examined by electron microscopy after the administration of CDDP (B) and NC-6004 (C). In rats given CDDP, widespread degenerations as indicated by loss of microtubules, loss of filaments, degeneration in the cytoplasm of Schwann cells (), and an irregular inner loop () were seen. On the other hand, animals given NC-6004 exhibited nearly normal electron micrographs of the sciatic nerve as the control animals. (D) Changes in relative body weight. Data were derived from the same rats as those used in the present study (control (×), CDDP (•), and NC-6004 (○)). (E) The Pt concentration in the sciatic nerve. Rats were given CDDP (▪) (5 mg kg−1, n=5), NC-6004 (□) (an equivalent dose of 5 mg kg−1 CDDP, n=5), or 5% glucose (n=2), all i.v. twice a week, four administrations in total. On day 3 after the final administration, a segment of the sciatic nerve was removed and the Pt concentration in the sciatic nerve was measured by ICP-MS. Body weight changes are expressed as the mean±s.e. The other data are expressed as the mean±s.d. *P<0.05, **P<0.001, NS: not significant.

Mentions: Neurophysiological examination revealed that MNCVs in animals given 5% glucose, CDDP, and NC-6004 were 44.2±3.5, 40.94±5.08, and 40.62±0.63 m s−1, respectively. No significant difference was found among the groups with respect to MNCV. Furthermore, SNCVs in animals given 5% glucose, CDDP, and NC-6004 were 42.86±8.07, 35.48±4.91, and 43.74±5.3 m s−1, respectively. Animals given NC-6004 showed no delay in SNCV as compared with animals given 5% glucose. On the other hand, animals given CDDP showed a significant delay (P<0.05) in SNCV as compared with animals given NC-6004 (Figure 5A). In addition, histopathological examination with electron microscopy revealed degenerations, as manifested by electron photomicrographs indicating degenerative changes, for example, loss of microtubules, degeneration in the cytoplasm of Schwann cells, loss of filaments, and an irregular inner loop, in approximately 80% of myelinated segments of the sciatic nerve from animals given CDDP. On the other hand, animals given NC-6004 exhibited nearly normal electron photomicrographs of the sciatic nerve as the control animals did (Figure 5B and C). These results indicate that NC-6004 reduced peripheral neurotoxicity as compared with CDDP. Furthermore, regarding body weight change as an indication of general toxicity, furthermore, the NC-6004 administration groups showed significant inhibition of body weight decrease (P<0.001) as compared with the CDDP administration group (P<0.001) (Figure 5D).


Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats.

Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, Nishiyama N, Kataoka K, Naito S, Kakizoe T - Br. J. Cancer (2005)

Neurotoxicity of CDDP and NC-6004 in rats. Rats (n=5) were given CDDP (2 mg kg−1), NC-6004 (an equivalent dose of 2 mg kg−1 CDDP), or 5% glucose, all i.v. twice a week, 11 administrations in total. (A) Sensory nerve conduction velocity and MNCV of the sciatic nerve at week 6 after the initial administration (control (), CDDP (•), and NC-6004 (□)). Histopathological changes of the sciatic nerve were examined by electron microscopy after the administration of CDDP (B) and NC-6004 (C). In rats given CDDP, widespread degenerations as indicated by loss of microtubules, loss of filaments, degeneration in the cytoplasm of Schwann cells (), and an irregular inner loop () were seen. On the other hand, animals given NC-6004 exhibited nearly normal electron micrographs of the sciatic nerve as the control animals. (D) Changes in relative body weight. Data were derived from the same rats as those used in the present study (control (×), CDDP (•), and NC-6004 (○)). (E) The Pt concentration in the sciatic nerve. Rats were given CDDP (▪) (5 mg kg−1, n=5), NC-6004 (□) (an equivalent dose of 5 mg kg−1 CDDP, n=5), or 5% glucose (n=2), all i.v. twice a week, four administrations in total. On day 3 after the final administration, a segment of the sciatic nerve was removed and the Pt concentration in the sciatic nerve was measured by ICP-MS. Body weight changes are expressed as the mean±s.e. The other data are expressed as the mean±s.d. *P<0.05, **P<0.001, NS: not significant.
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Related In: Results  -  Collection

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fig5: Neurotoxicity of CDDP and NC-6004 in rats. Rats (n=5) were given CDDP (2 mg kg−1), NC-6004 (an equivalent dose of 2 mg kg−1 CDDP), or 5% glucose, all i.v. twice a week, 11 administrations in total. (A) Sensory nerve conduction velocity and MNCV of the sciatic nerve at week 6 after the initial administration (control (), CDDP (•), and NC-6004 (□)). Histopathological changes of the sciatic nerve were examined by electron microscopy after the administration of CDDP (B) and NC-6004 (C). In rats given CDDP, widespread degenerations as indicated by loss of microtubules, loss of filaments, degeneration in the cytoplasm of Schwann cells (), and an irregular inner loop () were seen. On the other hand, animals given NC-6004 exhibited nearly normal electron micrographs of the sciatic nerve as the control animals. (D) Changes in relative body weight. Data were derived from the same rats as those used in the present study (control (×), CDDP (•), and NC-6004 (○)). (E) The Pt concentration in the sciatic nerve. Rats were given CDDP (▪) (5 mg kg−1, n=5), NC-6004 (□) (an equivalent dose of 5 mg kg−1 CDDP, n=5), or 5% glucose (n=2), all i.v. twice a week, four administrations in total. On day 3 after the final administration, a segment of the sciatic nerve was removed and the Pt concentration in the sciatic nerve was measured by ICP-MS. Body weight changes are expressed as the mean±s.e. The other data are expressed as the mean±s.d. *P<0.05, **P<0.001, NS: not significant.
Mentions: Neurophysiological examination revealed that MNCVs in animals given 5% glucose, CDDP, and NC-6004 were 44.2±3.5, 40.94±5.08, and 40.62±0.63 m s−1, respectively. No significant difference was found among the groups with respect to MNCV. Furthermore, SNCVs in animals given 5% glucose, CDDP, and NC-6004 were 42.86±8.07, 35.48±4.91, and 43.74±5.3 m s−1, respectively. Animals given NC-6004 showed no delay in SNCV as compared with animals given 5% glucose. On the other hand, animals given CDDP showed a significant delay (P<0.05) in SNCV as compared with animals given NC-6004 (Figure 5A). In addition, histopathological examination with electron microscopy revealed degenerations, as manifested by electron photomicrographs indicating degenerative changes, for example, loss of microtubules, degeneration in the cytoplasm of Schwann cells, loss of filaments, and an irregular inner loop, in approximately 80% of myelinated segments of the sciatic nerve from animals given CDDP. On the other hand, animals given NC-6004 exhibited nearly normal electron photomicrographs of the sciatic nerve as the control animals did (Figure 5B and C). These results indicate that NC-6004 reduced peripheral neurotoxicity as compared with CDDP. Furthermore, regarding body weight change as an indication of general toxicity, furthermore, the NC-6004 administration groups showed significant inhibition of body weight decrease (P<0.001) as compared with the CDDP administration group (P<0.001) (Figure 5D).

Bottom Line: In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP.On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004.These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

ABSTRACT
In spite of the clinical usefulness of cisplatin (CDDP), there are many occasions in which it is difficult to continue the administration of CDDP due to its nephrotoxicity and neurotoxicity. We examined the incorporation of CDDP into polymeric micelles to see if this allowed the resolution of these disadvantages. Cisplatin was incorporated into polymeric micelles through the polymer-metal complex formation between polyethylene glycol poly(glutamic acid) block copolymers and CDDP (NC-6004). The pharmacokinetics, pharmacodynamics, and toxicity studies of CDDP and NC-6004 were conducted in rats or mice. The particle size of NC-6004 was approximately 30 nm, with a narrow size distribution. In rats, the area under the curve and total body clearance values for NC-6004 were 65-fold and one-nineteenth the values for CDDP (P<0.001 and 0.01, respectively). In MKN-45-implanted mice, NC-6004 tended to show antitumour activity, which was comparable to or greater than that of CDDP. Histopathological and biochemical studies revealed that NC-6004 significantly inhibited the nephrotoxicity of CDDP. On the other hand, blood biochemistry revealed transient hepatotoxicity on day 7 after the administration of NC-6004. Furthermore, rats given CDDP showed a significant delay (P<0.05) in sensory nerve conduction velocity in their hind paws as compared with rats given NC-6004. Electron microscopy in rats given CDDP indicated the degeneration of the sciatic nerve, but these findings were not seen in rats given NC-6004. These results were presumably attributable to the significantly reduced accumulation of platinum in nerve tissue when NC-6004 was administered (P<0.05). NC-6004 preserved the antitumour activity of CDDP and reduced its nephrotoxicity and neurotoxicity, which would therefore seem to suggest that NC-6004 could allow the long-term administration of CDDP where caution against hepatic dysfunction must be exercised.

Show MeSH
Related in: MedlinePlus