Cytotoxic effects of temozolomide and radiation are additive- and schedule-dependent.

Abstract

PURPOSE:

Despite aggressive therapy comprising radical radiation and temozolomide (TMZ) chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor, particularly if tumors express O(6)-methylguanine-DNA-methyltransferase (MGMT). The interactions between radiation and TMZ remain unclear and have important implications for scheduling and for developing strategies to improve outcomes.

METHODS AND MATERIALS:

Factors determining the effects of combination therapy on clonogenic survival, cell-cycle checkpoint signaling and DNA repair were investigated in four human glioma cell lines (T98G, U373-MG, UVW, U87-MG).

RESULTS:

Combining TMZ and radiation yielded additive cytotoxicity, but only when TMZ was delivered 72 h before radiation. Radiosensitization was not observed. TMZ induced G2/M cell-cycle arrest at 48-72 h, coincident with phosphorylation of Chk1 and Chk2. Additive G2/M arrest and Chk1/Chk2 phosphorylation was only observed when TMZ preceded radiation by 72 h. The ataxia-telangiectasia mutated (ATM) inhibitor KU-55933 increased radiation sensitivity and delayed repair of radiation-induced DNA breaks, but did not influence TMZ effects. The multiple kinase inhibitor caffeine enhanced the cytotoxicity of chemoradiation and exacerbated DNA damage.

CONCLUSIONS:

TMZ is not a radiosensitizing agent but yields additive cytotoxicity in combination with radiation. Our data indicate that TMZ treatment should commence at least 3 days before radiation to achieve maximum benefit. Activation of G2/M checkpoint signaling by TMZ and radiation has a cytoprotective effect that can be overcome by dual inhibition of ATM and ATR. More specific inhibition of checkpoint signaling will be required to increase treatment efficacy without exacerbating toxicity.

• Authors: Anthony J Chalmers, Elliot M Ruff, Christine Martindale, Nadia Lovegrove, Susan C Short
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 75 Issue 5 Pg. 1511-9 (Dec 01 2009) ISSN: 1879-355X [Electronic] United States
• PMID: 19931733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
• Antineoplastic Agents, Alkylating
• Cell Cycle Proteins
• DNA-Binding Proteins
• Morpholines
• Neoplasm Proteins
• Pyrones
• Tumor Suppressor Proteins
• Caffeine
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• Protein Kinases
• Checkpoint Kinase 2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• Protein Serine-Threonine Kinases
• Temozolomide

Topics

• Antineoplastic Agents, Alkylating (administration & dosage, adverse effects)
• Ataxia Telangiectasia Mutated Proteins
• Caffeine (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Line, Tumor (radiation effects)
• Checkpoint Kinase 1
• Checkpoint Kinase 2
• Combined Modality Therapy (adverse effects)
• DNA Repair (drug effects)
• DNA-Binding Proteins (antagonists & inhibitors)
• Dacarbazine (administration & dosage, adverse effects, analogs & derivatives)
• Drug Administration Schedule
• G2 Phase (drug effects, radiation effects)
• Glioblastoma (enzymology, radiotherapy)
• Humans
• Morpholines (pharmacology)
• Neoplasm Proteins (metabolism)
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Phosphorylation
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrones (pharmacology)
• Radiation Tolerance (drug effects)
• Temozolomide
• Tumor Stem Cell Assay
• Tumor Suppressor Proteins (antagonists & inhibitors)