The experimental neuroprotectant leukaemia inhibitory factor (LIF) does not compromise antitumour activity of paclitaxel, cisplatin and carboplatin.
OBJECTIVE
Peripheral neuropathy caused by the anticancer agents cisplatin and paclitaxel is a significant dose-limiting toxicity of these drugs. The growth factor leukaemia inhibitory factor (LIF) has neuroprotectant activity in preclinical models of nerve injury and degeneration and is now in a phase II trial in chemotherapy-induced peripheral neuropathy (CIPN). It is therefore important to ensure that LIF neither inhibits the antitumour activity of these drugs, nor stimulates tumour growth.


METHODS
Mature female Dark Agouti rats were implanted subcutaneously with a mammary carcinoma, DAMA. It was confirmed that the tumour expressed LIF receptors by reverse transcriptase polymerase chain reaction. Paclitaxel was administered at a dose of 5 mg/kg daily for 6 days, cisplatin at a dose of 3 mg/kg twice weekly and carboplatin at a dose of 10 mg/kg twice weekly. The effect of LIF on tumour growth and response to chemotherapy was assessed at two doses (2 and 10 microg/kg per day). Peripheral neuropathy was assessed in terms of gait disturbance and tail-flick threshold.


RESULTS
Neither dose of LIF stimulated growth of control tumours. Mean tumour volumes were lower on day 14 in all paclitaxel-, cisplatin- and carboplatin-treated groups, compared to controls (ANOVA P<0.001). LIF did not interfere with this antitumour effect. Cisplatin- and paclitaxel-treated groups had developed increasing tail-flick thresholds by day 14. These manifestations of sensory neuropathy were prevented by LIF administration.


CONCLUSIONS
These results suggest that LIF may be safely used in human trials as a neuroprotectant for patients receiving cisplatin, paclitaxel and carboplatin without concern for impairment of antitumour effect.
Boyle
F M
FM
Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia. franb@med.usyd.edu.au
Beatson
C
C
Monk
R
R
Grant
S L
SL
Kurek
J B
JB
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007279:Injections, Subcutaneous; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental; D017239:Paclitaxel / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats
D000972:Antineoplastic Agents, Phytogenic; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin