maxacalcitol and Carcinoma--Squamous-Cell

Vitamin A and D(3) have a very strong differentiation induction effect.. We examined the anti tumor effect on head and neck squamous cell carcinoma (HNSCC) by treatment with several vitamins having strong differentiation induction effects in vitro.. We used KB cell that an oral floor squamous cell carcinoma, vitamins as all-trans retinoic acid (ATRA), 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), 1alpha,25(OH)(2)D(3) (calcitriol) and 22-oxa-1,25-(OH)(2)D(3) (OCT). We determined receptors of vitamin A and D(3) using RT-PCR. Furthermore, we investigated the proliferation of tumor cells in concentration dependency using [3H]TdR uptake method, apoptosis and apoptosis related factors using TUNEL method and real-time PCR, cell cycle changes using flow cytometry, changing of the sensitivity of using MTT method, cytokine production and the angiogenesis factor using ELISA, by treatment with these vitamins.. The deficit of RAR-beta was found in the KB cell. Each vitamin suppressed the cell proliferation, induced apoptosis, and cell cycle arrest, upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor; survivin.. These results support the idea that vitamin A, D(3) and their derivatives are useful for preventing and/or treating patients with HNSCC.

Topics: Angiogenesis Inducing Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Calcitriol; Carcinoma, Squamous Cell; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cisplatin; Cytokines; Flow Cytometry; Fluorouracil; Head and Neck Neoplasms; Humans; In Situ Nick-End Labeling; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tretinoin; Vitamin A; Vitamin D

Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 microg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cachexia; Calcitriol; Calcium; Carcinoma, Squamous Cell; Diphosphonates; Drug Synergism; Humans; Hypercalcemia; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Pamidronate; Pancreatic Neoplasms; Parathyroid Hormone-Related Protein; Pharyngeal Neoplasms; Proteins

Humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung, is mediated by the parathyroid hormone-related peptide (PTHrP). This study was undertaken to determine whether 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and two nonhypercalcemic analogues. EB1089 and 22-oxa-1,25(OH)(2)D(3) (OCT), suppress PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. All three compounds (1) decreased steady-state PTHrP mRNA and secreted peptide levels via a transcriptional mechanism; (2) modulated promoter activity of 1,25(OH)(2)D(3)-responsive DNA sequences; and (3) activated the vitamin D receptor (VDR) both in vitro and in vivo. Thus, EB1089 and OCT inhibit PTHrP gene expression in NCI H520 cells and modulate gene expression through the same mechanism as 1,25(OH)(2)D(3), namely, activation of the VDR. 1,25(OH)(2)D(3) is hypercalcemic in vivo. However, the noncalcemic analogues EB1089 and OCT have a therapeutic potential through suppression of PTHrP gene transcription.

Topics: Antineoplastic Agents; Calcitriol; Carcinoma, Squamous Cell; Gene Expression; Humans; Hypercalcemia; Lung Neoplasms; Parathyroid Hormone-Related Protein; Proteins; Receptors, Calcitriol; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured