抗癌劑(nitrogen mustard, methotrexate, 5-fluorouracil)가 肝再生, 皮膚創傷治유 및 骨髓에 미치는 影響

Abstract

[한글]

[영문]

Although it is still far from the goal, a great advance has been made in the field of cancer chemotherapy during the past decade, and numerous chemical and biological agents have been preyed to lave anticancerous effects.

At present, anticancerous agents can be divided into 6 major groups: 1) Alkylating agents, 2) Antimetabolites, 3) Antibiotics, 4) Hormones, 5) Radioisotopes, and 6) Other miscellaneous agents Some of the agents act rather selectively to certain cells, while others affect by virtue of their cytotoxic and antimetabolic action (Goodman and Gilman 1965).

Because of many common metabolic pathways between cancer cells and normal cells, many anticancerous drugs accompany untoward effect to normal tissue as well. especially to those actively regenerating tissues such as bone marrow, intestinal epithelium, fetal tissue, etc. (Heiderberger et al. 1757, Cantarow et al. 1958, Paschkis et al. 1959). Therefore, the dose of anticancerous agents has to be strictly controlled.

In clinical practice, chemotherapeutic agents are applied mostly in palliative purposes rather than radical treatment in the patient of disseminated cancer However, recently, chemotherapeutic agents are being used for the radical treatment

by regional perfusion technique (Clarkson and Lawrence 1761), or in purpose of obtaining shrinkage of a large tumor to enable to operate radically Furthermore, it is being attempted to use chemotherapeutic agents in adjuvant to the cancer surgery to prevent spread of tumor cells and destroy possible residual tumor cells at the surgery (Moore and Kendo 1958, McDonald 1960).

Present investigation is designed to study the influence of nitrogen mustard, methotrexate, and 5-fluorouracil on wound healing, regeneration of the liver, and the regeneration of the bone marrow when these drugs are administered in combination with a surgical procedure.

Materials and Methods

Albino rats of 270 to 300 gms were divided Into 4 groups, and treated as follows:

Group I : 15 rats were subjected to partial hepatectomy only.

Group Ⅱ : 15 rats, partial hepatectomy plus nitrogen mustard.

Group Ⅲ : 15 rats, partial hepatectomy plus methotrexate.

Group Ⅳ : 15 rats, partial hepatectomy plus 5-fluorouracil.

Partial hepatectomy was performed by the method of Higgins and Anderson (1931),removing entire median and left lateral lobes of the liver under ether anesthesia through 4 cm long skin incision at midline of the abdominal wall. After hepatectomy, 10 ml of 5% dextrose in saline were injected into the peritoneal cavity, and the incision was closed with double suture, peritoneum with muscle layer and the skin separately All operative procedures were carried out with aseptic precaution.

Nitrogen mustard was given once by intravenous injection through tail vein just after the hepatectomy in a dose of 0.4 mg per kg. Methotrexate was given orally for five days in a dose of 0.3 mg per kg per day The first dose was given one day before the operation, and the remaining doses were given for four consecutive days from the day after the operation. And 5-fluorouracil was given intraperitoneally in a dose of 20mg per kg per day for five days as for methotrexate.

Animals were killed at the 5th, 15th, and 25th day after the hepatectomy in each groups by ether anesthesia. Tissue from the skin wound, the liver, the bone marrow and other organs were fixed in 4% neutral formalin, and microsections were made after paraffin embedding In 6 μ thickness. Hematoxylin and eosin staining was performed to all sections for microscopical examinations.

Water content of the liver resected at operation and removed at necropsy was determined by drying the liver to a constant weight. Changes of body weight and wound length were also recorded.

Results and Summary

Body weight was decreased slightly at the fifth day after the hepatectomy, but begun to increase from the 15th day and returned to preoperative level at the 25th day after the operation in partial hepatectomy control group. But all groups treated with anticancerous drugs showed greater reduction of body weight which did not return to normal level at the 25th day after the hepatectomy,

The weight of the resected liver ranged from 2.96 to 6.84 ems (57.3 to 72.6 percent of the estimated original weight of the liver). In the control group, the liver regenenated to 95% of the estimated original weight and about 2.5 times of the liver left after the partial hepatectomy at the 5th day. At the 15th day it

increased to 3.43 times of the liver left after the partial hepatectomy and 100% of the estimated original weight, while it became slightly lesser than original weight at the 25th day, indicating the maximum increase was achieved at around the 15th

day after partial hepatectomy. The groups treated with anticancerous drugs showed moderate inhibition of weight gain of the liver until the 15th day. but at the 25th day the weight of the liver exceeded to that of the estimated original weight

indicating a rebound hyperplasia after the depression of regenerating activity in earlier period.

The water content of the rejected liver and the liver removed at the necropsy showed slight increase during the period of active regeneration, but no significant difference between each experimental groups was observed.

The length of the skin incision wound became progressively shortened as the days precede, and no statistical difference was observed between each experimental groups.

Microscopical observations of the liver at each intervals showed inhibiting effect of anticancerous agents on the regeneration of the hepatic cells and increased damaging effect to the liver cells at earlier period. But the final picture at the 25th day was not notably different from that of control group. The signs of damage was most marked at the 5th day, and the signs of regeneration was also marked at the 5th and 15th day in the control group. The proliferation of the Kupffer cells was also observed and most marked at the 15th day, without being

affected significantly by the administration of the drugs.

Microscopical findings of the strain wound showed slightly delayed epithelial regeneration in drug treated groups. But in the dermis and muscle layer abscess formation and inflammatory reaction were lesser In the groups treated with methotrexate and 5.flourouracil while the groups of control and nitrogen mustard

treatment showed marked tendency of abscess formation with marked inflammatory reaction. In the methotrexate and 5.fluorouracil treated groups, focal coagulation necrosis along incision wound margin was observed Instead of abscess formation. The diminished abscess formation is probably due to the lack of leukorytes to be

mobilized due to the damage of the bone marrow.

The bone marrow showed marked congestion and hypoplasia until the 15th day in the groups treated with methotrexate and 5.fluorouracil, whereas control and nitrogen mustard treated groups showed hyperplastic marrow even at the 5th day. At the 25th day all groups showed hyperplastic marrow.

In summary, data obtained by present investigation showed that combined administration of methotrexate or 5-fluorouracil with surgical procedures, partial hepatectomy, in rats inhibited regeneration of the liver cells and epithelial cells of the skin, inflammatory response in the dermis of the skin, and marked damage to the bone marrow until the 15th day after the surgery. But thereafter, rebound hyperplasia of the liver and bone marrow was observed. Therefore, ill-effect of antioancerous agents on surgical injury, If any, is transient and reversible without adverse effect on the final outcome of wound healing with the dose used in this study.