E Paclitaxel intravenously 175 mg m2 on days 1 and 8 of 21 day cycle reported in control arm of phase III breast cancer trial versus gemcitabinepaclitaxel combination40 f Nausea and vomiting reported as a combined adverse event

benchmark nucleoside antimetabolite 5-FU, its prodrug capecitabine, the nucleoside analog gemcitabine, which has supplanted 5-FU as the standard of care in pancreatic cancer, and the antifolate pemetrexed. Also for comparison, representative adverse events for paclitaxel, which acts by inhibiting microtubule formation, are included. The antimetabolite drugs act by inhibiting processes in rapidly dividing cells, in both tumors and normal tissue. Thus, the observed toxicities tend to be associated with tissues that undergo relatively frequent cell division, such as bone marrow, gastrointestinal tract, and hair. A significant number of patients in the trials discontinued treatment due to the adverse events, indicating another challenge in the clinical use of such drugs.

An additional hurdle for all chemotherapies is adapting the preclinical dosing regimen to the clinic. Efficacy doses for oncology drugs are determined in rodents (usually mice), and maximum tolerated doses are determined in mice, rats, dogs, or other species as warranted by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the drug in discovery phase. Again, due to differences in metabolism between species, the predictive ability of these models is limited. For example, preclinical evaluation of gemcitabine found it to have antitumor activity in several tumor xenografts, including breast (MX-1), colon (CX-1, HC-1, and GC3), NSCLC (Calu-6, LX-1, and NCI-H460), and pancreas (HS766T, PaCa-2, and PANC-1).30 The dosing regimens in these mouse models required 80-160 mg kg 1 of gemcitabine administered intraperitoneally every third day for 4 cycles. In contrast, the optimal dosing in humans for gemcitabine as a single agent in phase III trials for pancreatic cancer was found to be 1000mgm_2 administered intravenously over 30 min once weekly for up to 7 weeks.31

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