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The time course and duration of action of drugs used in cancer chemotherapy are greatly influenced by the molecular and biochemical properties of enzymes associated with their metabolism. Variation in the response of individual patients to cancer chemotherapeutic agents is in large measure due to genetic and environmental factors that impinge on specific enzymes belonging to the two major classes of drug metabolizing enzymes. Current knowledge of the molecular biology and biochemistry of phase I drug metabolizing enzymes (cytochrome P450, flavin-containing and xanthine oxidases, NADPH quinone reductase, and aldehyde and dihydropyridine dehydrogenases), and phase II enzymes (glucuronosyl-, sulfo-, N-acetyl-, and glutathione transferases, and hydrolases) is reviewed briefly. Advances in understanding genetic and environmental factors that influence activities of phase I and phase II pathways of drug metabolism are discussed in the first sections of this review followed by a consideration of the influence of drug metabolism on the actions of agents currently used in the treatment of cancer. Emphasis is given to drugs that have recently been introduced into the armamentarium of cancer chemotherapy including: inhibitors of chromatin function, target-based inhibitors of signal transduction and cyclin-dependent kinases, and angiogenesis inhibitors acting on metalloproteinases, epithelial cell growth, angiogenesis stimulation, and endothelial-specific integrins.

was suggested that the formation of a greater amount of hepatic 4-OH-E2 relative to that of 2-OH-E2 is related to the higher susceptibility of the ACI rat to E2-induced mammary tumors as 4-OH-E2 but not 2-OH-E2 is carcinogenic in the Syrian hamster kidney (7–9), and 4-OH-E2 is more carcinogenic towards the uterus of CD-1 mice than is 2-OH-E2 (10). Elevated 4-hydroxylation of E2 is observed in the Syrian hamster kidney (11,12) and in the CD-1 mouse uterus (13) and pituitary (14), all of which organs are susceptible to E2 carcinogenesis. Moreover, when compared with normal biopsies of breast tissues, elevated ratios of 4-OH-E2 to 2OH-E2 formation have been reported in human breast tumor samples (15,16). In the present report, we describe and compare the patterns of E2 hydroxylation in liver microsomes from the highly estrogen-sensitive female ACI rat with patterns in microsomes from the less estrogen-sensitive female Sprague–Dawley rat strain. Because of the potential importance of the high 4hydroxylation of E2 in a rat strain that is highly sensitive to E2-induced mammary carcinogenesis, we have made an attempt to confirm and extend the studies of Wilson and Reed (4). The data presented herein, however, indicate that liver microsomal preparations from female ACI rats hydroxylate E2 predominantly in the 2-position, and only a very small amount of 4-OH-E2 is formed. Materials and methods

Mechanistic and structural comparisons of five catalytic monoclonal antibodies generated from the same hybridoma fusion indicated that all five hydrolyze phenyl acetate by subtle variations of the same mechanism. All of the antibodies showed a pre-steady-state multi-turnover burst in which kcat and Km declined but kcat/Km did not change. The burst of one of the antibodies, 20G9, has previously been found to result from inhibition by the product, phenol. Although all of the antibodies showed the burst, their individual values for kcat, Km, and hapten Ki differed substantially. Three of the antibodies that were investigated for the effect of pH on kcat showed an acid limb pK of 9.5-9.6. Substrate inhibition was seen in four of the five antibodies. Variable region nucleotide sequencing of the heavy and light chains confirmed that all five antibodies were structurally similar and also revealed several potentially critical tyrosines. Despite their structural similarities, analysis of their sequences suggested that the antibodies are products of distinct, independent rearrangements of immunoglobulin gene segments that took place in different progenitor B cells. A plot of Ki for hapten inhibition vs Km/kcat for substrate hydrolysis for the mechanistically related antibodies ("isoabzymes") gave a linear relationship suggesting a catalytic role for transition-state complementarity. Taken together with previous work [Martin et al. (1991) Biochemistry 30, 9757-9761], the data conform to a mechanism in which the antibodies exploit both transition-state complementarity and an acyl-tyrosyl intermediate during phenyl acetate hydrolysis.