Abstract
Hyperthermia enhances thecytotoxic effect ofsomechemotherapeutic agents by various mechanisms (Johnson & Pavelec, 1973;Hahn,1975). Ina series ofexperiments studying theeffect ofcyclophosphamide (CY)atvarious temperatures, theeffect oftwoormoretreatments was investigated. Ithasbeendemonstrated that administration of somedrugs induces resistance toasubsequent administration ofthedrug(Schimke, 1984; Goldie & Coldman, 1984), and thathyperthermia alsoinduces resistance tosomechemotherapeutic agents (Morgan etal., 1979; Donaldson etal., 1978). Animals were10to12weekoldC3Hf/Sed micederived fromourdefined flora mousecolony. Theywerekeptinthe samefacility throughout theduration oftheexperiments. Sterilized mousepellets andacidified andvitamin-K fortified waterwereprovided adlibitum. Theearly generation isotransplants ofafibrosarcoma whicharose spontaneously in aC3Hf/Sed mouse, FSa-II wereused. Single cell suspensions wereprepared bya trypsinization procedure andtransplanted intothefoot. Hyperthermia wasadministered by immersing theanimals' feet intoawater bathwheredesired temperatures weremaintained bya constant temperature circulator (Lauda, modelMS,WestGermany) (Urano etal., 1980). Animals werenotanaesthetised forhyperthermia treatment. Tumoursweretreated whentheyreached anaverage diameter of4mm (35mm3)andtheTG (tumour growth) time, orthetimerequired foratumourtoreach 1000 mm3 after thelast treatment day,wasdetermined onthetumourregrowth curve foreachtumour. Then,themedian TG time wascalculated foreachgroupbylogit analysis (Urano etal., 1980). Approximately 7 to10animals wereusedforeach datumpoint andallexperiments wererepeated atleast once. The testagentwas cyclophosphamide (CY)(Mead Johnson, Syracuse, NY).Thisagent wasselected since its plasmahalf-time islonger incomparison withother alkylating agents (Begg & Smith, 1984). Itwasdissolved in distilled waterandinjected intraperitoneall y. Animals with4mm FSa-II tumours received onetofive daily treatments ofCY alone, combined heatandCY,or combined glucose, hyperthermia andCY treatments. A CY doseof50mgkg-1 eachwasgiven i.p. 30minbefore hyperthermia, anda glucose doseof5mgg-1eachwasgiven 60minbefore heattreatment. Hyperthermia wasat41.5°C for60min, whichgives amaximumenhancement fortheCY treatment (Uranoetal.,1985). Therationale forthe administration ofglucose isgiven elsewhere (Urano & Kim, 1983). Our previous experiments indicated thathyperglycaemia enhances thecytotoxic effect ofCY asaresult of reduced tumourtissue pH (Urano etal., 1985; Rheeetal., unpublished data). Thedose-response curve forsingle doses ofCY appears to beexponential, whilethoseforcombined treatments are biphasic ordownward concave (solid symbols inFigure 1). Daily treatments shownbyopensymbols anddotted lines
Highlights
Animals were 10 to 12 week old C3Hf/Sed mice derived from our defined flora mouse colony
Hyperthermia was at 41.5°C for 60min, which gives a maximum enhancement for the CY treatment (Urano et al, 1985)
The dose response curve for one to five daily CY doses alone showed a negative slope, indicating that the FSa-II tumour responded poorly to doses 2 to 5 and regrew during the treatment period, the tumour responded to the 1st CY dose as evidenced by a prolongation of the TG time from 9.5 days to 11 days (50mgkg-1 CY)
Summary
Animals were 10 to 12 week old C3Hf/Sed mice derived from our defined flora mouse colony. Animals with 4mm FSa-II tumours received one to five daily treatments of CY alone, combined heat and CY, or combined glucose, hyperthermia and CY treatments. A CY dose of 50mgkg-1 each was given i.p. 30min before hyperthermia, and a glucose dose of 5 mg g-1 each was given 60min before heat treatment.
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