The Research On Effects Of Chemotherapeutic Drugs On Small Arteries And Microcirculation

Objective:Toxic side-effects of chemotherapy treatment can not be avoided systemic damage during medical practice. The side effects cause systemic multi-organ damages including blood system, circulatory system, nervous system, and etc.. The side effects of drugs may cause limb skin or flap necrosis after chemotherapy or surgery and make patients suffer more. The main cause of limb skin or surgical area skin necrosis may be in related to the local ischemia that caused by artery and micro-circulation damages resulted in chemotherapeutic drugs. These direct vascular morphological damage studies are developed. This experiment modeled by rabbit chemotherapeutic treatment. The scheme of rabbit chemotherapeutic treatment and dosage are designed according to mimicking human body. The chemotherapeutic drug adopted was FAC (5-fluorouracil, adriamycin, cyclophosphamide), the common used drug in clinical chemotherapy for breast cancer. Rabbit's limb small artery and microcirculation injuries and restorations were found at different time points after chemotherapy. From the observation, thereby we can calculate safety time interval from the chemotherapy to performing operation.Methods:Twenty-eight healthy rabbits aged 24 weeks of both sexes with body weight of 2000-2500g were randomly divided into seven groups of four. Adopt normal human mammary cancer chemotherapeutic prescription: FAC Cyclophosphamide, Adriamycin (Doxorubicin), 5-fluorouracil. Convert human surface area dose into the rabbit's dose. The experimental group rabbits were given chemotherapeutic drugs through ear-edged intravenous drip according to the assigned period while the control group rabbits were given normal saline. Take samples of small and medium arteries, nerve terminal skin and hypoderm from the incision below the knee joint of hind limbs after anesthesia respectively on the third day, 7th day, 14th day, 28th day and 56th day after a course of treatment. perform morphologic observes: HE staining, PDGF-βand collagen typeⅠ, scored the immunohi-stochemical indicators. Observed the limbs and microcirculation injuries. Observed their recoveries at the different time points respectively and contrast with the control group. Before taking vessel samples, cut a piece of skin and hypoderm for HE staining. observed inflammatory cell infiltration and angiotelectasia, congestion and edema under an optical microscope.Results:The control group's endothelial cells were found in regular form and arrangement; there is not any cell shrinkage, dissolution and swelling. Endothelial cells and internal elastic layers bonded strongly. There is not any endothelial cell detachment, the endothelial cell ring-shape-lined regularly along the vessel wall. A small amount of scattered lymphocytes can be found in subcutaneous tissue.Observing the experimental group on the third day after a course of treatment: vascular cell degeneration and necrosis were found; proliferation of outer membrane appears; a small amount of endothelial cells detached; vacuolar degeneration of smooth muscle shows cytoplasmic structure disappeared; most nuclei closed to the cell membrane; cells'arrangement direction disordered, some ring-shaped arrangements could be seen. Slight vascular dilatation and congestion happened in the subcutaneous tissue, also local tissue edema. A small amount of scattered lymphocytes could be seen in the tissue.Observing on the sample 7th day after a course of treatment: vascular cells degeneration and necrosis were found; out membrane proliferated obviously; endothelial cells detached more frequently; the number of endothelial cells decreased; smooth muscle cells vacuoles- change became serious. The cells were disarranged. Some samples'smooth muscle layer was in significant edema. mild vascular dilatation and congestion in subcutaneous tissue. of a small amount of local tissue edema. Mild hyperplasia of collagen fibers scattered in granulocytes.Observing on the sample 14th day after a course of treatment: endothelial cell detachment decreased, proliferative response to outer membrane was obviously seen; the number of endothelial cells was approximately the same compared with that of the 7th day; the cells were slightly in disordered arrangement; smooth muscle is still in swelling. Cell arrangement a little disorder, blood vessels in subcutaneous tissue dilated slightly; local tissue was in edema; subcuticular fibrous tissue proliferated; a small amount of scattered lymphocytes could be seen in the tissue.Observing on the sample the 28th day after a course of treatment: cell and connective tissue began to proliferate; near the outer membrane of smooth muscle proliferation returned to normal, endothelial cells scattering decreased distinctly, exfoliated cells decreased vacuolization of smooth muscle cells changed significantly restored, but the cell arrangement direction significantly recovered; there was not any significant edema in smooth muscle layer; the capillaries in subcutaneous tissue were slightly dilated; epithelial cells arranged in order; collagenous fiber bundles could be seen occasionally.Observing on the sample 56th day after a course of treatment: the sample condition was close to that of the control group. The necrotic smooth muscles were completely replaced by proliferated smooth muscles. There were not obvious endothelial cells scattering, the endothelial cells had a solid bond with internal elastic layer. No tissue edema was found. Vascular smooth muscle cells were spindle-shaped, arranged regularly along the blood vessel wall in circle. Vascular reparation was almost completed. Epithelial cells arranged in order. There were a small amount of scattered lymphocytes beneath the epithelial cells. Immunohistochemical score shows vascular morphology returned to normal in 56 days after a course of treatment.Conclusions:The experiment showed: intravenous dripping chemotherapeutic drugs with the dosage mimicking human body one course may cause rabbit's limb arteriolar wall injury. The injury was an acute process. Chemotherapy chemotherapeutic drugs caused parts of vascular endothelial necrosis, subcutaneous tissue inflammation cell infiltration. 14 days after the chemotherapy, the vessel wall showed a repairing proliferation; 28 after days the chemotherapy, the repairing proliferation markedly enhanced; 56 days after chemotherapy, the injured blood vessels were almost returned to normal state in morphology. This suggested: the vessels'state changed following the vascular wall dynamic repairing. The changes of vessels may be reversible. The most sensitive injury was in arterial endothelial cells, then smooth muscle cells. The chemotherapeutic drug impacted less on subcutaneous tissue compared that of blood vessels. It also suggested: a surgery should performed four weeks after chemotherapy to avoid this four weeks serious vessels'injury period. This experiment refers a selection of operating time. This experiment only provides a direct observation of a blood vessel cells'and soft tissues'injury and recovery conditions. It has not any straight relation with success rate of clinical surgery.