Improved therapeutic index of cisplatin by procaine hydrochloride

M. Esposito, R. A. Fulco, P. Collecchi, A. Zicca, A. Cadoni, F. Merlo, R. Rosso, A. Sobrero

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Abstract

The local anesthetic procaine hydrochloride (P.HCl) had little effect effect on the sensitivity of P388 leukemic cells to cisplatin (DDP) in vitro, but the simultaneous administration of DDP and P.HCl (40 mg/kg) to BDF 1 mice produced 50% lethal dose (LD 50) and 90% lethal dose (LD 90) values approximately two times higher than those observed with DDP alone. DDP-P.HCl diluted in water and administered intraperitoneally (IP) on day 1 and on days 1 and 5 to BDF 1 mice bearing P388 leukemic cells produced 33% and 50% cure rates, respectively, at the maximum tolerated dose (16 mg/kg for the single administration and 10 mg/kg given on days 1 and 5). In contrast under the same conditions, the cure rates obtained with DDP alone (10 mg/kg for the single administration and 8 mg/kg given on days 1 and 5) were 17% and 9%, respectively. Protection from DDP nephrotoxicity seems to be the explanation for the higher doses of DDP that mice can tolerate when DDP is given simultaneously with P.HCl. In fact, the increased blood urea nitrogen (BUN) levels observed 4-7 days following a single IP administration of DDP (8 or 16 mg/kg), as well as the tubular degenerative changes detected by light microscopy, were not observed when the same doses of DDP were given simultaneously with P.HCl. Since DDP nephrotoxicity is known to be reduced when the drug is diluted in 0.9% NaCl solution, we compared the combinations DDP-P.HCl in water, and DDP and DDP-P.HCl in 0.9% NaCl solution. The antitumor activity of DDP diluted in water and administered with P.HCl was similar to that observed in mice treated with DDP alone diluted in 0.9% NaCl solution. However, further improvement of the therapeutic index was achieved after the administration of DDP-P.HCl diluted in 0.9% NaCl solution; this regimen produced a cure rate of 67% (12 of 18 animals). The clinical relevance of these findings is strengthened by the observation that similar results were obtained when P.HCl was given by the intravenous route.

Original languageEnglish
Pages (from-to)677-684
Number of pages8
JournalJournal of the National Cancer Institute
Volume82
Issue number8
Publication statusPublished - 1990

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Procaine
Cisplatin
Therapeutics
Lethal Dose 50
Water
Maximum Tolerated Dose
Blood Urea Nitrogen
Local Anesthetics
Microscopy
Light

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Esposito, M., Fulco, R. A., Collecchi, P., Zicca, A., Cadoni, A., Merlo, F., ... Sobrero, A. (1990). Improved therapeutic index of cisplatin by procaine hydrochloride. Journal of the National Cancer Institute, 82(8), 677-684.

Improved therapeutic index of cisplatin by procaine hydrochloride. / Esposito, M.; Fulco, R. A.; Collecchi, P.; Zicca, A.; Cadoni, A.; Merlo, F.; Rosso, R.; Sobrero, A.

In: Journal of the National Cancer Institute, Vol. 82, No. 8, 1990, p. 677-684.

Research output: Contribution to journalArticle

Esposito, M, Fulco, RA, Collecchi, P, Zicca, A, Cadoni, A, Merlo, F, Rosso, R & Sobrero, A 1990, 'Improved therapeutic index of cisplatin by procaine hydrochloride', Journal of the National Cancer Institute, vol. 82, no. 8, pp. 677-684.
Esposito M, Fulco RA, Collecchi P, Zicca A, Cadoni A, Merlo F et al. Improved therapeutic index of cisplatin by procaine hydrochloride. Journal of the National Cancer Institute. 1990;82(8):677-684.
Esposito, M. ; Fulco, R. A. ; Collecchi, P. ; Zicca, A. ; Cadoni, A. ; Merlo, F. ; Rosso, R. ; Sobrero, A. / Improved therapeutic index of cisplatin by procaine hydrochloride. In: Journal of the National Cancer Institute. 1990 ; Vol. 82, No. 8. pp. 677-684.
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abstract = "The local anesthetic procaine hydrochloride (P.HCl) had little effect effect on the sensitivity of P388 leukemic cells to cisplatin (DDP) in vitro, but the simultaneous administration of DDP and P.HCl (40 mg/kg) to BDF 1 mice produced 50{\%} lethal dose (LD 50) and 90{\%} lethal dose (LD 90) values approximately two times higher than those observed with DDP alone. DDP-P.HCl diluted in water and administered intraperitoneally (IP) on day 1 and on days 1 and 5 to BDF 1 mice bearing P388 leukemic cells produced 33{\%} and 50{\%} cure rates, respectively, at the maximum tolerated dose (16 mg/kg for the single administration and 10 mg/kg given on days 1 and 5). In contrast under the same conditions, the cure rates obtained with DDP alone (10 mg/kg for the single administration and 8 mg/kg given on days 1 and 5) were 17{\%} and 9{\%}, respectively. Protection from DDP nephrotoxicity seems to be the explanation for the higher doses of DDP that mice can tolerate when DDP is given simultaneously with P.HCl. In fact, the increased blood urea nitrogen (BUN) levels observed 4-7 days following a single IP administration of DDP (8 or 16 mg/kg), as well as the tubular degenerative changes detected by light microscopy, were not observed when the same doses of DDP were given simultaneously with P.HCl. Since DDP nephrotoxicity is known to be reduced when the drug is diluted in 0.9{\%} NaCl solution, we compared the combinations DDP-P.HCl in water, and DDP and DDP-P.HCl in 0.9{\%} NaCl solution. The antitumor activity of DDP diluted in water and administered with P.HCl was similar to that observed in mice treated with DDP alone diluted in 0.9{\%} NaCl solution. However, further improvement of the therapeutic index was achieved after the administration of DDP-P.HCl diluted in 0.9{\%} NaCl solution; this regimen produced a cure rate of 67{\%} (12 of 18 animals). The clinical relevance of these findings is strengthened by the observation that similar results were obtained when P.HCl was given by the intravenous route.",
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