Parathyroid hormone: a novel tool for treating bone marrow depletion in cancer patients caused by chemotherapeutic drugs and ionizing radiation.
Between 1958 and the late 1970s it was learned that PTH (the parathyroid hormone) could directly stimulate the initiation of DNA replication by murine CFU-S (colony-forming unit-spleen) cells via cyclic AMP, stimulate the proliferation of normal and X-irradiated murine and rat bone marrow cells, control hematopoiesis, and increase the survival of X-irradiated mice and rats when injected any time between 18h before and 3h after X-irradiation. Since then, it has been shown that the hematopoietic stem cell niche consists of PTH receptor-bearing, osteoblastic trabecular bone-lining cells that maintain the stem cells' (HSCs') proliferatively quiescent 'stemness' by various gene up-regulating and down-regulating signals caused by the tight adhesion of the HSCs to the osteoblastic niche-lining cells. Stimulating the osteoblastic lining cells with recombinant human PTH-(1-34) (Forteo) causes a cyclic AMP-mediated enlargement of the HSC pool and promotes bone marrow transplant engraftment and growth and the survival of lethally irradiated mice. But this is only the beginning of the exploitation of the PTHs for marrow engraftment. It must now be determined whether the marrow engraftment-enhancing action of this potent bone growth-stimulating PTH can be extended from mice to rats and monkeys. It must be determined whether two other PTH peptides, rhPTH-(1-84) [Preos]and [Leu(27)]cyclo(Glu(22)-Lys(26))hPTH-(1-31)NH(2) [Ostabolin-C]) are as effective as or better than rhPTH-(1-34)(Forteo). Since, all three peptides are on the market, or nearing the market, for safely and strongly stimulating bone growth and treating osteoporosis one or all of them may become valuable tools for safely promoting the engraftment of peripherally harvested HSCs in cancer patients whose bone marrows have been 'emptied' by chemotherapeutic drugs or ionizing radiation.
Whitfield
James F
JF
Institute for Biological Sciences, National Research Council of Canada, Building M-54, Montreal Road Campus, Ottawa, Ont., Canada K1A 0R6. pthosteo@rogers.com
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001853:Bone Marrow / Q000187:drug effects* / Q000528:radiation effects; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011839:Radiation, Ionizing
D000970:Antineoplastic Agents; D010281:Parathyroid Hormone