Red blood cell polyamine levels and host toxicity during continuous alpha‐difluoromethylornithine infusion

Ota, David M.; Grossie, V. Bruce; Ajani, Jaffer A.; Stephens, L. Clifton; Nishioka, Kenji

doi:10.1002/ijc.2910380215

Cited by 9 publications

(3 citation statements)

References 18 publications

(14 reference statements)

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“…All rats were anesthesized (Ketamine | 50 mg/kg, i.m.) 4 We have previously demonstrated that this ratio protected the rat from DFMO-induced throm-bocytopenia but did not affect the antitumor activity. When the tumor width was 1.0 cm, two dimensional measurements (cm) were taken every other day and the weight (g) calculated using the formula-length X width 2 x IA [3].…”

Section: Methods and Proceduresmentioning

confidence: 90%

“…DFMO in a rat-model and in man is thrombocytopenia [4,5]. DFMO in a rat-model and in man is thrombocytopenia [4,5].…”

Section: Discussionmentioning

confidence: 99%

“…Although these low molecular weight cations are required for cell growth and proliferation, their precise biological role has yet to be completely elucidated [1,2]. The major toxicity of parenteral DFMO in our experimental model was a dose-and time-dependent thrombocytopenia [4]. The activity of mammalian ODC and the synthesis of putrescine is significantly decreased by the irreversible inhibition of difluoromethylornithine (DFMO).…”

Section: Introductionmentioning

confidence: 99%

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Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

et al. 1991

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The dose limiting toxicity of difluoromethylornithine (DFMO), when administered by continuous infusion, is thrombocytopenia. DFMO-induced antitumor activity and thrombocytopenia were time- and dose-dependent up to 1700 mg/kg/d when administered continuously for 12 days. Concomitant ornithine administration (at selected molar ratios to DFMO) ameliorated thrombocytopenia induced by DFMO at a dose of 2000 mg/kg/day without adversely affecting its antitumor activity. The purpose of this study was to determine if ornithine could ameliorate the thrombocytopenia of higher DFMO doses and increase the efficacy of DFMO. Fischer 344 male rats with a transplantable sarcoma in the right flank were given 2000 and 3500 mg/kg/d DFMO alone or with ornithine at a molar ratio of 0.4 for 8 days by continuous infusion. Concomitant ornithine infusion overcame the thrombocytopenia that was induced by either dose of DFMO without reducing the antitumor activity against the sarcoma. The antitumor activity, tumor polyamine levels, and tumor S-adenosylmethionine decarboxylase activity did not consistently change with increasing doses of DFMO or with the addition of ornithine to the infusion regimen. These results demonstrate that the thrombocytopenia induced by doses of DFMO greater than 2000 mg/kg/d can be ameliorated without compromising the antitumor activity.

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Section: Methods and Proceduresmentioning

confidence: 90%

“…DFMO in a rat-model and in man is thrombocytopenia [4,5]. DFMO in a rat-model and in man is thrombocytopenia [4,5].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

et al. 1991

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Polyamine‐directed preferential nutritional repletion of normal tissues in tumor‐bearing hosts

Nishioka

Grossie

Ajani

et al. 1988

Intl Journal of Cancer

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Our previous study demonstrated that total parenteral nutrition (TPN) increases erythrocyte (RBC) polyamines selectively in cancer patients but not in non-cancer patients, suggesting that these changes may relate to tumor presence. We therefore studied the possible relationship between RBC polyamine levels and potential tumor growth induced by TPN. In addition, we attempted to control tumor growth during TPN with alpha-difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), in a fibrosarcoma-bearing rat model. Rats in a control group received chow ad libitum for 3 weeks and their tumors grew exponentially. A restricted intake (RI) tumor-bearing group received 8 g chow per day per rat; this produced malnourished rats in which tumor growth significantly slowed. The third group (RI----TPN) received the RI diet for 2 weeks and TPN for 1 week, which resulted in an increase in tumor growth. The last group (RI----TPN + DFMO) received a 2-week RI regimen and 1-week TPN plus DFMO regimen, which inhibited tumor growth to the level of the RI group due to the addition of DFMO (1 g/kg/day). Although the addition of TPN to the RI regimen markedly increased tumor ODC activity, as well as tumor putrescine and RBC putrescine levels, the addition of DFMO to the RI----TPN regimen entirely abolished these increases. Despite DFMO treatment, liver ODC activity in RI----TPN + DFMO group was unaffected. The plasma albumin level, an indicator of host nutrition, of the RI----TPN + DFMO group was significantly higher than that of the RI group. Liver, spleen, kidney and total body weights of the RI----TPN or RI----TPN + DFMO group were significantly higher than those of the RI group. These results indicate that TPN can enhance tumor growth in malnourished hosts and that the addition of DFMO to TPN can effectively control this TPN-enhanced tumor growth, leading to preferential nutritional repletion of the host.

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Mechanisms of cellular resistance to cisplatin

Hospers

Mulder

Vries

1988

Med. Oncol. & Tumor Pharmacother.

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Red blood cell polyamine levels and host toxicity during continuous alpha‐difluoromethylornithine infusion

Cited by 9 publications

References 18 publications

Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

Polyamine‐directed preferential nutritional repletion of normal tissues in tumor‐bearing hosts

Mechanisms of cellular resistance to cisplatin

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