I am currently trying to study tumor regression in mice xenograft models using treatment with hydroxyurea.
There seem to be limited publications and I am trying hard to determine a suitable dose to be given IP to the mice.
Does anyone have experience using hydroxyurea in xenograft mice? What dose do you use and what is your drug schedule?
Thanks in advance!
Effects of double and multiple doses of hydroxyurea on mouse duodenum and mammary tumors.
Dethlefsen LA, Sorensen SP, Riley RM.
Abstract
Previous data on the effects of a single dose of hydroxyurea on C3H mouse duodenum and mammary tumors from a fast growing line (S102F) were used to predict times that may be optimal (i.e., minimize killing of the duodenal S-phase cells while enhancing the killing of tumor S-phase cells) for the administration of subsequent doses of hydroxyurea. These predicted protocols were tested by giving tumor-bearing mice injections of 2 doses at 24 hr intervals. A preliminary in vivo tumor treatment experiment was also done wherein multiple doses (up to 10) were given either at 12, 20, or 24 hr intervals with the mouse survival, body weights, and tumor volumes being recorded daily. The data show that partial cell synchronization was achieved in both tissues and the initial knetics of the surviving cells was essentially the same after a single dose, 2 doses, or 4 doses of hydoxyurea. Also, the different intervals between the 2 doses did not affect the timing of the initital peaks of DNA synthesis in partially synchronized cells; however, the height of the peaks was affected The results demonstrate that kinetic data can be useful for predicting optimal intervals for 2-dose regimes and probably multiple-dose regimes involving a single cell-cycle phase-speeific drug when applied to a mouse tumor model. However, the recovery phenomena in the respective tissues are extremely complicated and more animal tumor data need to be collected before one can make adquate use of cell-synchronizing agents and perturbed cellular kinetic data for routine clinical chemotherapy or combined modality therapy.
https://www.ncbi.nlm.nih.gov/pubmed/1116130
In vivo tests performed by the National Cancer Institute showed significant activity of hydroxyurea in leukemia L1210 (schedule: 74 mg/kg IP, once every 3 hrs/24 times, or 100 mg/kg IP, once daily for 9 days), in Gardner lymphoma 6C3HED (schedule: 90 mg/kg IP, once daily for 10 days) and in several other lymphohematopoietic cancers, but activity of hydroxyurea as a single agent is rather limited in solid tumors. These cases were syngeneic grafts of murine cancer cells and not xenografts. One tested xenograft was human mammary MX-1 tumor growing intrarenally in NU/NU mice and the schedule 400 mg/kg once daily for 10 days displayed considerable toxicity with modest anticancer efficacy. Therefore, I would not expect remarkable activity against human solid tumors xenografted into mice. On the other hand, hydroxyurea potentiates effect of radiation and it is sometimes used in combined chemo-radiotherapy of some squamous cell cancers, so combination with radiation can be considerably more efficacious in some xenografts.
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