Preclinical efficacy evaluations of XK-469: dose schedule, route and cross-resistance behavior in tumor bearing mice.

摘要: XK-469 is advancing to Phase I clinicaltrials. Preclinical studies were carriedout assist in clinical applications.Dose-schedule route testing: Singledose IV treatment with producedlethality (LD20 LD 100) above 142 mg/kg.Optimum required total dosages of350 600 mg/kg. Furthermore, highindividual (100 mg/kg)were poorly tolerated, producingsubstantial weight loss (8 18% of bodyweight), poor appearance, and slow recovery(8 12 days). A 1-hour infusion ofdosages more than 140 mg/kg, or BIDinjections 6 hrs apart, did not reducelethality. However, lower individualdosages 40 50 mg/kg/injection werewell tolerated could be given daily toreach an optimum dose minimaltoxicities. Likewise, 75 IVcould used every other day reachoptimal treatment. The necropsy profiles ofdeaths from toxic essentiallyidentical regardless schedule (deaths 4to 7 days post treatment). profileswere: paralytic ileus gastroparesis; GIepithelial damage; marrow toxicity.Interestingly, the key lethal events wererapidly reversible simple overcomewith everyother day. Based on these results, highdose, Q21day should avoided inclinical applications. Instead, a splitdose regimen recommended (e.g., daily,every day, twice weekly). XK-469was also well by oral route,requiring 35% higher PO reachthe same efficacy toxicity as producedIV. Cross-resistance studies: XK-469resistance was produced optimumtreatments implanted L1210 leukemiaover seven passage generations. Thisleukemia subline (L1210/XK469) had reducedsensitivity VP-16 (with 4.0 log killin L1210/XK469 compared an8.0 kill against L1210/0). It reduction sensitivityto 5-FU 2.0 theimplanted logkill Otheragents approximately active againstthe resistant tumor, including: Ara-C,Gemzar, Cytoxan, BCNU, DTIC, CisDDPT. No case collateral sensitivity wasobserved; i.e., no agent markedly moreactive sublineL1210/XK-469 parent tumorin mice.