Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model

<p>Abstract</p> <p>Background</p> <p>Skin manifestations of Tuberous Sclerosis Complex (TSC) cause significant morbidity. The molecular mechanism underlying TSC is understood and there is evidence that systemic treatment with rapamycin or other mTOR inhibitors may be a useful approach to targeted therapy for the kidney and brain manifestations. Here we investigate topical rapamycin in a mouse model for TSC-related tumors.</p> <p>Methods</p> <p>0.4% and 0.8% rapamycin ointments were applied to nude mice bearing subcutaneous, TSC-related tumors. Topical treatments were compared with injected rapamycin and topical vehicle. Rapamycin levels in blood and tumors were measured to assess systemic drug levels in all cohorts.</p> <p>Results</p> <p>Treatment with topical rapamycin improved survival and reduced tumor growth. Topical rapamycin treatment resulted in systemic drug levels within the known therapeutic range and was not as effective as injected rapamycin.</p> <p>Conclusion</p> <p>Topical rapamycin inhibits TSC-related tumor growth. These findings could lead to a novel treatment approach for facial angiofibromas and other TSC skin lesions.</p

Rapamycin levels in tumor samples after treatment with topical or IP rapamycin

Rapamycin levels in tumor homogenates from indicated treatment groups were measured 24 hours (A, C) and 48 hours (B, D) after the final dose of rapamycin. Panels C and D are enlarged versions of the boxed-in data in panels A and B respectively.<p><b>Copyright information:</b></p><p>Taken from "Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model"</p><p>http://www.biomedcentral.com/1471-5945/8/1</p><p>BMC Dermatology 2008;8():1-1.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266897.</p><p></p

Rapamycin whole blood levels after treatment with topical and IP rapamycin

A) Whole blood rapamycin levels from tumor bearing animals from indicated treatment groups. Rapamycin levels were measured 24 hours after the final dose of rapamycin. B) Whole blood rapamycin levels were measured in cohorts of control mice with no tumors. As indicated, levels were measured 24 hours after either one or three doses of topical rapamycin. In some groups, Elizabethan collars or bandages were used to prevent ingestion of rapamycin ointment. All animals had rapamycin levels >3 ng/ml. The slightly higher levels in the Elizabethan collar group suggests that ingestion is not a major issue. The lower levels in the bandage groups suggests that the bandage polymer can affect drug absorption. C) Whole blood rapamycin levels were also measured 48 hours after the final dose in tumor bearing animals. D) In three of the control, non-tumor bearing groups, rapamycin levels were measured at 48 hours following their final treatment to compare to tumor bearing animals.<p><b>Copyright information:</b></p><p>Taken from "Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model"</p><p>http://www.biomedcentral.com/1471-5945/8/1</p><p>BMC Dermatology 2008;8():1-1.</p><p>Published online 28 Jan 2008</p><p>PMCID:PMC2266897.</p><p></p

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-1

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-4

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p> the difference in growth pattern between the two treatment cohorts in the first 20 days of treatment. c) Survival curve for the early rapamycin and late rapamycin-treated cohorts. d) Data shown in table format

Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779-6

<p><b>Copyright information:</b></p><p>Taken from "Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779"</p><p>http://www.biomedcentral.com/1471-2210/7/14</p><p>BMC Pharmacology 2007;7():14-14.</p><p>Published online 6 Nov 2007</p><p>PMCID:PMC2213639.</p><p></p>t was administered. Whole blood, brain, kidney, and tumor tissue were collected at necropsy. a) Blood, brain, and kidney rapamycin levels from cohorts treated with rapamycin or CCI-779 for four consecutive days and euthanized 2–4 hours after drug injection. b) Blood, brain, and kidney rapamycin levels from cohorts treated with rapamycin or CCI-779 for four consecutive days and euthanized 24 hours after drug injection. c) Tumor rapamycin levels from indicated cohorts treated with rapamycin or CCI-779 and euthanized 2–4 hours after drug injection. Rapa = rapamycin. This data is shown in table format with statistical analyses in Table 2