Peter F. Wadsworth

AZD2171: A Highly Potent, Orally Bioavailable, Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for the Treatment of Cancer

Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.

Organ weight data in juvenile and adult marmosets (Callithrix jacchus)

Organ weight data from 167 (82 male and 85 female) juvenile and adult common cotton-eared marmosets (Callithrix jacchus) is presented. The marmosets were bred in captivity and were used as untreated or vehicle control animals in safety evaluation studies carried out over an 8 year period.

Segmental aplasia of the vagina in the beagle bitch

Segmental aplasia of the vaginal mucosa was discovered in 3 beagle bitches at the end of a routine toxicological experiment. Anomalies of Müllerian duct development in the bitch are discussed.

Haematological, coagulation and blood chemistry data in red-bellied tamarins Saguinus labiatus

Haematology, coagulation and clinical chemistry data are reported for a group of male and female red-bellied tamarins (Saguinus labiatus). The tamarins were juvenile and young adults and were bred in captivity. High mean values for activities of alkaline phosphatase, alanine amino-transferase, aspartate aminotransferase and creatine kinase were noted. The findings are compared with data obtained from other members of the family Callitrichidae.

A case of endometriosis in the macaque diagnosed by nuclear magnetic resonance imaging

A case of spontaneous endometriosis was diagnosed in the pigtailed macaque (Macaca nemestrina nemestrina) with the aid of high-field (2·35 T), T2-weighted (TE50), C1H2-suppressed, oblique nuclear magnetic resonance imaging (MRI). Postmortem histology was obtained. A variety of endometriotic lesions was seen with MRI, including extrauterine hyperintense apparently cystic regions, extrauterine hypointense regions apparently associated with intracellular paramagnetic iron proteins, and an enlarged myometrium exhibiting adenomyosis foci.

Renal aplasia and hypoplasia in the rhesus monkey (Macaca mulatta)

Unilateral renal aplasia or hypoplasia was discovered in 3 wild-caught rhesus monkeys at the end of routine toxicological experiments. No clinical abnormalities were evident and the opposite kidneys had undergone compensatory hypertrophy and hyperplasia.