UKCCCR Guidelines for the welfare of animals in experimental neoplasia

Workman, Paul; Balmain, Allan; Hickman, J.A.; McNally, N. J.; Rohas, A M; Mitchison, N. A.; Pierrepoint, C. G.; Raymond, Ruth; Rowlatt, C; Stephens, Tom; Wallace, Jessica L.; Straughan, Donald W.

doi:10.1007/bf00047059

Cited by 129 publications

(121 citation statements)

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“…The mice were maintained in laminar flow rooms with constant temperature and humidity. Experimental protocols were approved by the Ethics Committee for Animal Experimentation of the Istituto Nazionale per lo Studio e la Cura dei Tumori (Milan, Italy) according to the United Kingdom Coordinating Committee on Cancer Research Guidelines (Workman et al, 1998).…”

Section: In Vivo Studiesmentioning

confidence: 99%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

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The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always 485%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg À1 . In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD ¼ 10 mg kg À1 ). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

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Section: In Vivo Studiesmentioning

confidence: 99%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

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“…The potential for abdominal distention and pain induced by the increasing abdominal tumor mass has also been addressed (5,11,12). Abdominal carcinomatosis in humans has been reported to be painful (9).…”

Section: Monoclonal Antibody Production In Murine Ascitesmentioning

confidence: 99%

Evaluation of hollow fiber bioreactors as an alternative to murine ascites production for small scale monoclonal antibody production

Jackson

Trudel

Fox

et al. 1996

Journal of Immunological Methods

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Monoclonal antibody (MAb) production via the growth of ascitic tumors in mice has been the time-honored technique for producing small scale, research laboratory quantities of MAbs. There are many disadvantages associated with MAb production in murine ascites, including animal welfare concerns. Small scale, commercially available, hollow fiber bioreactor systems, which appear to have advantages over other in vitro cell culture techniques, have recently been introduced. To the author's knowledge, these bioreactor systems have not been independently evaluated as a potential alternative to the in vivo production of MAbs in murine ascites. The first objective of this study was to characterize the clinicopathologic changes in mice associated with the in vivo production of MAbs. Five different hybridoma cell lines were grown in groups of 20 mice. Mice were primed with 0.5 ml pristane intraperitoneally 14 days prior to inoculation of 1 x 106 hybridoma cells.Abdominal paracentesis was performed a maximum of 3 times for collection of ascites from each mouse; ascites volumes were recorded. Clinical observations, body weight measurements, and postmortem examinations were performed. Incidence and severity of clinical abnormalities increased with time. Disseminated intraabdominal seeding of tumor and/or solid tumor masses were observed at postmortem examination. The second objective of the study was to compare MAb production in mice versus hollow fiber bioreactor systems to determine the feasibility of these systems as potential alternatives to the use of mice. Three hybridoma cell lines were grown in each of three different commercially available hollow fiber bioreactor systems and in groups of 20 mice. Bioreactors were harvested 3 times weekly for 65 days and were monitored by cell counts, cell viability and media glucose consumption. Time and materials logs were maintained. Time spent in labor and materials costs were greater for the bioreactors than the mice. The mean antibody concentration, as determined by ELISAs, in mouse ascites versus the range of mean concentrations for the 3 bioreactor systems for each cell line were as follows: cell line 2B11, 4.22 mg/ml vs. 0.71 to 1.31 mg/ml; cell line 3C9, 4.07 mg/ml vs. 1023.06 mg. Significant clinicopathologic changes in mice were associated with MAb production in ascites. Although time and materials costs were greater for the bioreactors, these results suggest that hollow fiber bioreactor systems merit further investigation as potentially viable alternatives to the use of mice for MAb production.2 ACKNOWLEDGEMENTS

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“…9,16 Male SCID (C.B-17/IcrHanHsd-Prkdc-scid) mice were Germany). To test novel antitumor agents in a setting that reflects the human disease better than subcutaneous models, we used our previously designed orthotopic model for prostate cancer using PSA-positive luciferasemarked LNCaP luciferase-neomycin tumor cells orthotopically implanted into the prostates of SCID mice.…”

Section: Methodsmentioning

confidence: 99%

In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP)

Elsadek¹,

Graeser²,

Esser³

et al. 2010

Prostate Cancer Prostatic Dis

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PSA, which is overexpressed in prostate carcinoma, represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this study, we report on the in vivo antitumor efficacy of an efficacious albumin-binding prodrug of doxorubicin (PSA9) that incorporates p-aminobenzyloxycarbonyl (PABC) as a self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, which serves as a substrate for PSA. The prodrug is cleaved very efficiently by PSA releasing H-Ser-Leu-PABC-doxorubicin and subsequently doxorubicin in PSA-positive cell lysates and prostate tumor homogenates as the final cleavage product. PSA9 at 3 Â 6 mg kg À1 doxorubicin equivalents (intravenous) was compared with conventional doxorubicin at equitoxic doses (at 3 Â 3 mg kg À1 ; intravenous) in an orthotopic mouse model of prostate cancer using LNCaP lentiviral luciferase-neomycin cells transduced with luciferase. Whereas doxorubicin did not show any efficacy against the primary tumor or metastases, the prodrug reduced the primary tumor by 30-50% and circulating PSA levels, and in addition, showed a pronounced reduction in lung and bone metastases by B77% and B96%, respectively, and a positive trend regarding the activity against liver and lymph-node metastases compared with control and doxorubicin-treated animals. The incorporation of PABC as a self-immolative spacer together with a PSA substrate demonstrates superior antitumor effects over doxorubicin attributed to an efficient cleavage by PSA releasing doxorubicin as the final active agent in prostate tumor homogenates. Using this approach for developing effective prodrugs against prostate cancer, is worthy of further preclinical optimization.

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UKCCCR Guidelines for the welfare of animals in experimental neoplasia

Cited by 129 publications

References 0 publications

IDN 5390: an oral taxane candidate for protracted treatment schedules

IDN 5390: an oral taxane candidate for protracted treatment schedules

Evaluation of hollow fiber bioreactors as an alternative to murine ascites production for small scale monoclonal antibody production

In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP)

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