Kanser tedavisinde teofilin

Teofilin, obstrüktif havayolu hastalıklarının tedavisinde kullanılan bir ilaçtır. Fosfodiesteraz enzimini inhibe ederek hücre içinde siklik AMP ‘nin yıkılmasını önler. Teofilinin olası faydalı etkileri bronş düz kas gevşemesi, artmış mukosiliyer transport, pulmoner hipertansiyonda azalma, diyafragma kasılma gücünde artış ve ventilasyonun santral uyarılmasıdır. Diğer yandan teofilin, insan meme kanseri hücrelerinde zamana ve konsantrasyona bağımlı olarak DNA sentezini azaltır. Teofiline maruz kalmış melanom hücreleri laminin veya tip IV kollagene daha düşük adezyon gösterir. Dolayısıyla teofilin melanom hücrelerinin sadece çoğalmasını değil aynı zamanda metastaz yapma yeteneklerini de baskılama potansiyaline sahiptir. Bu ilaç endotel hücre çoğalmasını engelleyerek neovaskülarizasyonu önler. Teofilinin diğer sitotoksik ilaçlarla kombine edilmesi akciğer kanseri olgularında kemoterapi için gereken etkili dozlarda azalma sağlayabilir. İlacın sisplatine bağlı nefrotoksisite sürecinde koruyucu etkileri olabilir. Ancak bu ilaç küçük hücreli akciğer kanseri hücrelerini inhibe ederken akciğer adenokarsinomu hücrelerini aktive edebilir. Teofilinin her bir akciğer kanseri üzerindeki gerçek etkisinin ortaya çıkması için geniş prospektif çalışmalara ihtiyaç vardır.

Anahtar Kelimeler:

Antikarsinojenik ajanlar, Çay, Siklik AMP, Akciğer neoplazmları, Teofilin

Theophylline in the treatment of cancer

Theophylline is a drug used for the treatment of obstructive airway diseases. It inhibits the enzyme phosphodiesterase, thereby preventing the intracellular break-down of cyclic AMP. Potentially beneficial therapeutic effects of theophylline include bronchial smooth-muscle relaxation, enhanced mucociliary transport, decrease in pulmonary hypertension, improved diaphragmatic contractility, and central stimulation of ventilation. On the other hand, theophylline evokes a concentration- and timedependent decrease in DNA synthesis in human breast cancer cells. Theophylline-treated melanoma cells exhibit low adhesion to laminin/collagen type IV. Consequently, theophylline possesses the capacity to inhibit not only cell proliferation, but also the metastatic behaviour of melanoma cells. This drug prevents neovascularization of the tumor by blocking endothelial cell proliferation. The combination of theophylline with cytotoxic drugs may permit a reduction in the effective dose needed in chemotherapy treatment of lung cancer patients. It has also a prophylactic effect on the nephrotoxicity due to cisplatin. However, this drug may inhibit small cell lung cancer cells but stimulate pulmonary adenocarcinoma cells. It is necessary to perform large, prospective studies for the exact role of theophylline on each type of lung cancer.

Keywords:

Anticarcinogenic Agents, Tea, Cyclic AMP, Lung Neoplasms, Theophylline,

PDF

___

1. Chung FL. The prevention of lung cancer induced by a tobacco-specific carcinogen in rodents by green and black Tea. Proc Soc Exp Biol Med, 1999; 220: 244-248.
2. Shafer SH, Phelps SH, Williams CL. Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors. Biochem Pharmacol, 1998; 56: 1229-1236.
3. Valenzuela MT, Mateos S, Ruiz de Almodovar JM, McMillan TJ. Variation in sensitizing effect of caffeine in human tumour cell lines after gamma-irradiation. Radiother Oncol, 2000; 54: 261-271.
4. VanderPloeg LC, Wolfrom DM, Welsch CW. Influence of caffeine on development of benign and carcinomatous mammary gland tumors in female rats treated with the
carcinogens 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea. Cancer Res, 1991; 51: 3399-3404.
5. Nomura M, Ichimatsu D, Moritani S, et al. Inhibition of epidermal growth factorinduced cell transformation and Akt activation by caffeine. Mol Carcinog, 2005; 44: 67-76.
6. Menon LG, Ingle AD, Gude RP. Tumor regression of B16F10 melanoma in vivo by prevention of neovascularization: study on theophylline. Cancer Biother Radiopharm, 2002; 17: 213-217.
7. Lentini A, Kleinman HK, Mattioli P, et al. Inhibition of melanoma pulmonary metastasis by methylxanthines due to decreased invasion and proliferation. Melanoma Res, 1998; 8: 131-137.
8. Hirsh L, Dantes A, Suh BS, et al. Phosphodiesterase inhibitors as anti-cancer drugs. Biochem Pharmacol, 2004; 68: 981-988.
9. Caraglia M, Marra M, Giuberti G, et al. Theophylline-induced apoptosis is paralleled by protein kinase A-dependent tissue transglutaminase activation in cancer cells. J Biochem (Tokyo), 2002; 132: 45-52.
10. Slotkin TA, Seidler FJ. Antimitotic and cytotoxic effects of theophylline in MDAMB- 231 human breast cancer cells. Breast Cancer Res Treat, 2000; 64: 259-267.
11. Crumpton TL, Seidler FJ, Slotkin TA. Generation of reactive oxygen species by xanthine derivatives in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat, 2001; 66: 143-146.
12. Nowell S, Sweeney C, Hammons G, Kadlubar FF, Lang NP. CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk. Cancer Epidemiol Biomarkers Prev, 2002; 11: 377- 383.
13. Merimsky O, Hirsh L, Dantes A, et al. Induction of apoptosis in non-small lung carcinoma cell line (H1299) by combination of anti-asthma drugs with gemcitabine and cisplatin. Int J Oncol, 2005; 26: 475-482.
14. Mabed M, Aref S, Fouda M, El- Sharawy S. Chlorambucil plus theophylline vs chlorambucil alone as a front line therapy for B-cell chronic lymphatic leukemia. Leuk Lymphoma, 2004; 45: 2029-2035.
15. Netherton SJ, Maurice DH. Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: implications in angiogenesis. Mol Pharmacol, 2005; 67: 263-272.
16. Maruno K, Absood A, Said SI. Vasoactive intestinal peptide inhibits human small-cell lung cancer proliferation in vitro and in vivo. Proc Natl Acad Sci USA, 1998; 95: 14373-14378.
17. Kaur G, Viallet J, Laborda J, et al. Growth inhibition by cholera toxin of human lung carcinoma cell lines: Correlation with GM1 ganglioside expression. Cancer Res, 1992; 52: 3340-3346.
18. Malki AM, Gentry J, Evans SC. Differential effect of selected methylxanthine derivatives on radiosensitization of lung carcinoma cells. Exp Oncol, 2006; 28: 16-24.
19. Jull BA, Plummer HK, Schuller HM. Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf- 1/MAP kinase pathway, resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells. J Cancer Res Clin Oncol, 2001; 127: 707-717.
20. Shute JK, Tenor H, Church MK, Holgate ST. Theophylline inhibits the release of eosinophil survival cytokines -- is Raf-1 the protein kinase A target? Clin Exp Allergy, 1998; 28: 47-52.
21. Schuller H M, Porter B, Riechert A, Walker K, Schmoyer R. Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers Lung Cancer, 2004; 45: 11-18.
22. Al-Wadei HA, Takahashi T, Schuller HM. Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2. Oncol Rep, 2006; 15: 431-435.
23. Schuller HM, Porter B, Riechert A. Beta-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J Cancer Res Clin Oncol, 2000; 126: 624-630.