Abstract
LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses.
Highlights
The present study examines the activity of flavone acetic acid against three mouse transplantable subcutaneous colon tumours (MAC) tumour lines
For in vivo experiments LM975, LM985 and cyclophosphamide were dissolved in physiological saline and methyl-CCNU in 10% ethanol/arachis oil at an appropriate concentration for a desired dose to be administered in 0.1 ml per lOg body weight
This study demonstrates that MAC 13 is highly sensitive to LM985 in vitro whereas MAC 1 5A cells are only moderately sensitive at a 1 h exposure
Summary
Pure strain NMRI mice (age 6-8 weeks) from our inbred colony were used. They were fed on CRM diet (Labsure, England) and water ad libitum. LM985 was received from the EORTC Screening & Pharmacology Group and further supplies were a gift from Dr W.R. Vezin, CRC Formulation Unit, University of Strathclyde. LM975 was a gift from Lipha (Lyon) via Professor S.B. Kaye, University of Glasgow. Positive control compounds methyl-CCNU and cyclophosphamide were gifts from the NCI and Boehringer, UK, respectively. For in vivo experiments LM975, LM985 and cyclophosphamide were dissolved in physiological saline and methyl-CCNU in 10% ethanol/arachis oil at an appropriate concentration for a desired dose to be administered in 0.1 ml per lOg body weight.
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