Capecitabine improves cancer cachexia and normalizes IL-6 and PTHrP levels in mouse cancer cachexia models.
OBJECTIVE
To clarify the potential of parathyroid hormone-related protein (PTHrP) and interleukin-6 (IL-6) as cachectic factors in a colon 26 model and the effects of capecitabine on cancer cachexia as determined by plasma levels of IL-6 and PTHrP and body weight loss.


METHODS
From two colon 26 sublines-cancer cachectic clone20 and non-cachectic clone5 plasma levels of PTHrP protein and mRNA expression levels in tumor tissues were compared. An IL-6 neutralizing antibody, a PTHrP neutralizing antibody, and capecitabine were administered into mice bearing clone20 and their anticachectic effects evaluated.


RESULTS
The plasma level of PTHrP protein in mice bearing clone20 was higher than that in mice bearing clone5. The expression level of PTHrP mRNA was 49-fold higher in tumor tissues of clone20 than of clone5, according to GeneChip analysis. PTHrP antibody as well as IL-6 antibody suppressed wasting of the body and gastrocnemius and adipose tissue weights. PTHrP antibody suppressed the induction of hypercalcemia but not hypoglycemia or elevation of IL-6, whereas IL-6 antibody suppressed the induction of hypoglycemia but not hypercalcemia or elevation of PTHrP. Capecitabine, a fluorinated pyrimidine anticancer agent, improved body wasting of mice bearing clone20 at a low dose with no reduction of tumor volume. Furthermore, capecitabine lowered the levels of PTHrP and IL-6 in plasma and suppressed hypoglycemia and hypercalcemia in this model. Capecitabine also showed anticachectic effects on cachexia in a cancer model induced by human cervical cancer cell line Y (also known as Yumoto).


CONCLUSIONS
PTHrP and IL-6 were found to be factors in the development of cachexia in a colon 26 cancer model, and capecitabine improved cancer cachexia by suppressing the plasma levels of IL-6 and PTHrP in colon 26 and Y cachectic models.
Fujimoto-Ouchi
Kaori
K
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceuticals Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. ohuchikor@chugai-pharm.co.jp
Onuma
Etsuro
E
Shirane
Masatoshi
M
Mori
Kazushige
K
Tanaka
Yutaka
Y
D000818:Animals; D002100:Cachexia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000069287:Capecitabine; D002460:Cell Line; D003110:Colonic Neoplasms / Q000150:complications*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006934:Hypercalcemia / Q000517:prevention & control; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D044162:Parathyroid Hormone-Related Protein / Q000097:blood*; D014407:Tumor Cells, Cultured; D015431:Weight Loss
D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil