Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for 'platinum-resistant' ovarian cancer.
Summary of "Inhibition of carboplatin-induced DNA interstrand crosslink repair by gemcitabine in patients receiving these drugs for 'platinum-resistant' ovarian cancer."
The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in 'platinum-resistant' ovarian cancer. Peripheral blood lymphocytes (PBLs) were sampled after drug administration to measure DNA interstrand crosslink formation and repair. PATIENTS AND
40 patients received carboplatin AUC4 followed by gemcitabine 1000 mg/m2 with a second dose of gemcitabine on day 8. PBLs were obtained in 12 patients before, and at intervals during the first cycle of chemotherapy. DNA crosslink formation and repair (unhooking) were measured by the single cell gel electrophoresis (comet) assay following ex vivo incubation.
The global response rate was 47% (RECIST rate: 29%; CA125 rate: 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA crosslinking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA crosslinks following administration of gemcitabine.
An enhanced activity of carboplatin in 'platinum-resistant' ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA crosslinks. Future studies should explore co-administration of these drugs, as this may be a more effective schedule.
UCL Cancer Institute, University College London.
This article was published in the following journal.
Name: Clinical cancer research : an official journal of the American Association for Cancer Research
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20719935
- DOI: http://dx.doi.org/10.1158/1078-0432.CCR-10-0832
Medical and Biotech [MESH] Definitions
Sos Response (genetics)
An error-prone mechanism or set of functions for repairing damaged microbial DNA. SOS functions (a concept reputedly derived from the SOS of the international distress signal) are involved in DNA repair and mutagenesis, in cell division inhibition, in recovery of normal physiological conditions after DNA repair, and possibly in cell death when DNA damage is extensive.
The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.
An organoplatinum compound that possesses antineoplastic activity.
Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.
Leukocyte Adherence Inhibition Test
Test for cell-mediated antitumor immunity and related serum blocking factors based on the finding that leukocytes from cancer patients, but not from controls, when mixed in vitro with antigenic extracts of tumors of the same histological type, undergo a diminution in their normal adherence to glass surfaces. Sera from tumor-bearing patients block the LAI reaction of their own leukocytes or those of other patients with the same type of tumor.
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