A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer.
(41/3696)
Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5-fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5-fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross-resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have been approved for clinical use within the last 3 years. (+info)
Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice.
(42/3696)
Phosphorylation of tyrosine residues on the epidermal growth factor (EGF) receptor (EGFr) is an important early event in signal transduction, leading to cell replication for major human carcinomas. CP-358,774 is a potent and selective inhibitor of the EGFr tyrosine kinase and produces selective inhibition of EGF-mediated tumor cell mitogenesis. To assess the pharmacodynamic aspects of EGFr inhibition, we devised an ex vivo enzyme-linked immunosorbent assay for quantification of EGFr-specific tyrosine phosphorylation in human tumor tissue specimens obtained from xenografts growing s.c. in athymic mice. When coupled with pharmacokinetic analyses, this measurement can be used to describe the extent and duration of kinase inhibition in vivo. CP-358,774 is an effective, orally active inhibitor of EGFr-specific tyrosine phosphorylation (ED(50) = 10 mg/kg, single dose). It has a significant duration of action, producing, on average, a 70% reduction in EGFr-associated phosphotyrosine over a 24-h period after a single 100 mg/kg dose. Inhibition of EGFr phosphotyrosine in an ex vivo assay format effectively estimates the potency and degree of inhibition of EGFr-dependent human LICR-LON-HN5 head and neck carcinoma tumor growth. Substantial growth inhibition of human tumor xenografts was achieved with p.o. doses of the compound (ED(50) = 10 mg/kg q.d. for 20 days). Combination chemotherapy with cisplatin produced a significant response above that of cisplatin alone with no detectable effects on body weight or lethal toxicity. Taken together, these observations suggest that CP-358,774 may be useful for the treatment of EGFr-driven human carcinomas. (+info)
Enzyme prodrug gene therapy: synergistic use of the herpes simplex virus-cellular thymidine kinase/ganciclovir system and thymidylate synthase inhibitors for the treatment of colon cancer.
(43/3696)
The goal of this study was to improve the therapeutic index of the herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system by the addition of thymidylate synthase (TS) inhibitors. For this, we assessed the potential of GCV to synergistically interact with 5-fluorouracil (5-FU), ZD1694 (Tomudex), and (E)-5-(2-bromovinyl)-2'-deoxyuridine in HSV-tk-expressing murine MC38 STK and human HT-29 STK colon carcinoma cell lines. Synergistic cell killing was observed in a clonogenic assay over most of the cytotoxic dose range by the median-effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). In a s.c. HT-29 STK xenograft tumor model, we demonstrated that the combination of GCV and 5-FU resulted in statistically significant enhanced animal survival over single-agent treatment. Furthermore, we showed that the combination of GCV and ZD1694 in association with the HSV-tk/GCV system was at least as effective as GCV/5-FU in vitro and in vivo. The mechanism for the observed synergy is most likely attributable to the increased GCV phosphorylation in the presence of the tested TS inhibitors. Our data suggest that the HSV-tk/GCV metabolic suicide gene transfer system could serve as an adjuvant of the presently used TS inhibitors, thus potentially improving the efficacy of present cancer gene therapy approaches. (+info)
In vivo toxicity and pharmacokinetic features of the janus kinase 3 inhibitor WHI-P131 [4-(4'hydroxyphenyl)-amino-6,7- dimethoxyquinazoline.
(44/3696)
4-(4'Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) is a potent and selective inhibitor of the Janus kinase 3, which triggers apoptosis in human acute lymphoblastic leukemia (ALL) cells. In this preclinical study, we evaluated the pharmacokinetics and toxicity of WHI-P131 in rats, mice, and cynomolgus monkeys. Following i.v. administration, the terminal elimination half-life of WHI-P131 was 73.2 min in rats, 103.4 min in mice, and 45.0 min in monkeys. The i.v. administered WHI-P131 showed a very wide tissue distribution in mice. Following i.p. administration, WHI-P131 was rapidly absorbed in both rats and mice, and the time to reach the maximum plasma concentration (tmax) was 24.8 min in rats and 10.0 min in mice. Subsequently, WHI-P131 was eliminated with a terminal elimination half-life of 51.8 min in rats and 123.6 min in mice. The estimated i.p. bioavailability was 95% for rats, as well as for mice. WHI-P131 was quickly absorbed after oral administration in mice with a tmax of 5.8 min, but its oral bioavailability was relatively low (29.6%). The elimination half-life of WHI-P131 after oral administration was 297.6 min. WHI-P131 was not acutely toxic to mice at single i.p. bolus doses ranging from 0.5-250 mg/kg. Two cynomolgus monkeys treated with 20 mg/kg WHI-P131 and one cynomolgus monkey treated with 100 mg/kg WHI-P131 experienced no side effects. Plasma samples from WHI-P131-treated monkeys exhibited potent antileukemic activity against human ALL cells in vitro. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a Janus kinase 3 inhibitor. Further development of WHI-P131 may provide the basis for new and effective treatment programs for relapsed ALL in clinical settings. (+info)
Determinants of activity of the antifolate thymidylate synthase inhibitors Tomudex (ZD1694) and GW1843U89 against mono- and multilayered colon cancer cell lines under folate-restricted conditions.
(45/3696)
The cytotoxicity and metabolic effects of two thymidylate synthase (TS) inhibitors, Tomudex (Raltitrexed, ZD1694) and GW1843U89, were studied in WiDr colon cancer cells under four different growth conditions: as standard monolayers and as postconfluent multilayers grown under either high (WiDr, 8.8 microM folic acid) or low (WiDr/F, 1 nM leucovorin) folate conditions. Both GW1843U89 and ZD1694 were 13-15-fold more active against WiDr/F than WiDr cells when cultured as monolayers (IC50s in WiDr/F cells were 0.22 and 0.39 nM, respectively). WiDr cells were markedly less sensitive to the drugs when grown as multilayers (4-15-fold), in contrast to the WiDr/F cells, which were equally sensitive. However, total growth inhibition could not be achieved in WiDr multilayers (concentration causing total growth inhibition > 10,000 nM), whereas in WiDr/F multilayers, it could be achieved at 0.42 nM ZD1694 and 150 nM GW1843U89. Growth conditions markedly affected the TS levels when using different enzyme assays. At nonsaturating substrate concentrations, the catalytic activity of TS was similar in mono- and multilayers grown under high folate conditions but lower in multilayers at saturating concentrations. In cells grown under low folate conditions, TS catalytic activity was 3-6-fold lower in multilayers than in monolayers. This was consistent with a decrease in the number of S-phase cells in multilayers. Western blotting revealed less pronounced (2-3-fold) differences in the TS protein content. Exposure of the cells for 24 h to the drugs increased the TS levels by 4-fold. Because this increase in TS levels might explain the decrease in sensitivity to the TS inhibitors, we measured TS inhibition (TSI) by the drugs in intact cells using the TS in situ assay. GW1843U89 was more active than ZD1694. However, after 4 h of exposure in WiDr/F mono- and multilayers, TSI was in the same range for both drugs [50% TSI (TSI50), 0.5-1.7 nM]. In WiDr cells, the TSI50 for ZD1694, but not GW1843U89, was 10 times higher in the multilayers as compared to the monolayers. Despite the increase in TS protein levels, the extent of TSI was similar or even more pronounced in both cell lines grown as either multi- or monolayers. Because the cells were grown under depleted and folate-rich conditions that may affect folate uptake, we measured folate transport using methotrexate (MTX) as the reference drug for the activity of the reduced folate carrier. MTX uptake was 4-fold lower in multilayers compared to monolayers in both WiDr and WiDr/F cells. Uptake of MTX was 5-fold more effective in WiDr/F cells than in WiDr cells in both mono-and multilayers. In conclusion, the resistance of WiDr multilayers to the novel antifolates ZD1694 and GW1843U89 may be due to the high folate medium concentrations, which may be responsible for impaired drug uptake along with less effective TSI. In contrast, WiDr/F monolayers and multilayers were very sensitive to these antifolates. These effects of folate homeostasis may explain some of the variable results seen in treatment of solid tumors with new antifolate TS inhibitors. (+info)
The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar.
(46/3696)
The gene encoding the multidrug resistance P-glycoprotein (P-gp) is duplicated in rodent species and the functional basis for this remains unresolved. Despite a high sequence similarity, the mouse P-gp1a and P-gp1b isoforms show distinct patterns of tissue distribution which suggest a specific role of the P-gp1b isoform in steroid transport. In the present study possible biochemical differences between the isoforms were directly investigated at the level of drug interaction. There was no detectable difference in the affinity or binding capacity of the two isoforms towards [3H]vinblastine at equilibrium. Similarly, the rate at which [3H]vinblastine associates with P-gp was indistinguishable between the two isoforms. Some modest differences were observed in the relative abilities of the multidrug-resistant (MDR) reversing agents CP100-356, nicardipine and verapamil to displace equilibrium [3H]vinblastine binding to P-gp1a and P-gp1b. The steroid hormone progesterone displayed a low affinity (Ki = 1.2 +/- 0.2 microM for P-gp1a and 3.5 +/- 0.5 microM for P-gp1b), suggesting an unlikely role as a physiological substrate. Thus the mouse isoforms do not appear to exhibit functional differences at the level of initial substrate interaction with protein. (+info)
Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates.
(47/3696)
Cellular methotrexate (MTX) resistance may cause treatment failure in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS). After short-term exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX (P +info)
Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older.
(48/3696)
PURPOSE: The surgical treatment of colorectal cancer (CRC) in elderly patients (age 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately. PATIENTS AND METHODS: Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of CRC patients receiving chemotherapy at the Royal Marsden Hospital. The cutoff age was 70 years. RESULTS: A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the 1,387 patients, 310 were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the two age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% v 29%, P =.19) and median FFS (164 v 168 days) were detected when the elderly were compared with younger patients. Median OS was 292 days for the elderly group and 350 days for the younger patients (P =.04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical. CONCLUSION: Elderly patients with good performance status tolerated adjuvant and palliative chemotherapy for CRC as well as did younger patients and had similar benefits from palliative chemotherapy. (+info)