A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

Abstract

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts—the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [14C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R2=0.95, p<0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p=0.02 and p=0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK), and [14C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14C]carboplatin formulation for the microdose was 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response.

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel

“…This result is similar to our previous observations in ovarian, lung, and bladder cancer cell lines as well as patient-derived xenograft models of bladder cancer and in bladder cancer patients, suggesting that the use of diagnostic microdosing to determine platinum sensitivity is applicable in multiple types of cancers in spite of them having differing etiologies and biologies. 61–64 Our AMS data provided information on the total drug-DNA adduct load without molecular information on the actual distribution of specific adduct types. Both carboplatin and oxaliplatin predominantly bind to N7 of guanine and adenine, but other adduction products are possible.…”

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism

“…Patients with NSCLC only have a 10–15% 1 year survival rate even under the best treatment 2. Platinum-based anticancer drugs are the major chemotherapeutics used for treating various cancers,3–5 including NSCLC 6–8. These drugs are believed to react with nuclear DNA (nDNA) and induce apoptosis by inhibiting nDNA replication and gene transcription 9.…”

“…2 Platinum-based anticancer drugs are the major chemotherapeutics used for treating various cancers, 3 – 5 including NSCLC. 6 – 8 These drugs are believed to react with nuclear DNA (nDNA) and induce apoptosis by inhibiting nDNA replication and gene transcription. 9 However, their clinical efficacy is severely undermined by drug resistance, 10 which results primarily from the decrease of cellular drug accumulation and increase of cellular self-repairation.…”

Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing

“…Additionally, these data bolster our group’s documented correlations between diagnostic microdosing-induced carboplatin-DNA adduct levels and clinical response and overall survival in lung and bladder cancer patients. 36,37…”