Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry

Our plain-English summary of Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry, by R.J. Parker, I. Gill, R. Tarone, et al (Carcinogenesis, 1991).

The study

• Authors: R.J. Parker, I. Gill, R. Tarone, J.A. Vionnet, S. Grunberg, F.M. Muggia, E. Reed
• Journal: Carcinogenesis
• Published: 1991;12(7):1253-8
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.

In plain English

This study did not examine asbestos; it measured DNA damage from platinum chemotherapy. In a University of Southern California phase 1 trial, 21 patients with various tumors received carboplatin on day 1 and cisplatin on day 3 of 28-day cycles. Coded blood samples were analyzed at the National Cancer Institute for platinum bound to white-blood-cell DNA. Seventeen could be compared on the level 24 hours after the first carboplatin dose. The six partial responders included both pleural mesothelioma patients. One of them had no objectively measurable disease at the start but was counted as a responder after marked tumor reduction, complete resolution of malignant effusions and marked clinical improvement. The responders had a median of 49.2 fmol per microgram of DNA, against 14.4 in the 11 non-responders (P = 0.0071). Combined across the four post-treatment measurement days, the summary P value was 0.00011. Combined total doses varied by less than twofold, but adduct levels varied widely between patients. The authors concluded that a person's innate ability to protect DNA substantially affects cancer drug resistance. They noted the small sample; only six patients were measured on all six days.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: prospective blinded laboratory study of patients treated in a phase 1 clinical trial
• Who was studied: 21 cancer patients treated at the Norris Cancer Center, University of Southern California. Of these, 19 were evaluable for disease response. Of those, 17 were evaluable for comparing response with the adduct level 24 hours after the first carboplatin dose. These 17 had 15 different tumor types, including 2 with pleural mesothelioma. Study dates are not given.
• Exposure: Chemotherapy, not asbestos. Carboplatin 200 to 480 mg/m2 on day 1 and cisplatin 50 or 75 mg/m2 on day 3 of 28-day cycles, at five dose levels. Platinum-DNA adducts in blood leukocyte DNA were measured by atomic absorption spectrometry.
• Main results:
  • 24 hours after the first carboplatin dose, the 6 responders had a median adduct level of 49.2 fmol per microgram DNA, compared with 14.4 in the 11 non-responders. The difference was statistically significant (two-sided P = 0.0071).
  • On the other post-treatment days, the difference between responders and non-responders was statistically significant at cycle 2 day 4 (P = 0.036). It was not significant at cycle 1 day 4 (P = 0.097) or cycle 2 day 2 (P = 0.198), which the authors called trends towards significance.
  • A summary comparison across the four post-treatment days (cycle 1 days 2 and 4, cycle 2 days 2 and 4) gave a two-sided P value of 0.00011, with higher adduct levels in responders.
  • Partial responses occurred in five tumor types: ovarian cancer, pleural mesothelioma, breast cancer, buccal mucosa cancer and esophageal cancer. One pleural mesothelioma patient (patient 5) had no objectively measurable disease at the start. That patient was counted as a responder because of marked reduction in tumor bulk, complete resolution of malignant effusions and marked improvement in clinical status.
  • The combined total doses varied by less than a factor of two, while adduct levels varied widely between patients.
  • Among patients with measurable adduct levels after the first carboplatin dose, levels varied 29-fold.
  • No correlation was observed between any toxicity and disease response. The authors did not show these data.
• The authors' conclusion: The authors concluded that an individual's innate ability to protect cellular DNA from DNA-damaging agents has a substantive impact on cancer drug resistance.
• Limitations the authors state:
  • The sample was small, and adducts were measured on all six study days for only six patients. Because not all patients were studied at all time points, the strength of the correlations might change under optimal conditions.
  • There was no clear relationship between the total platinum dose given and the adduct level.

Topics

Medical terms in this study, explained in our Lexicon: Carboplatin, Cisplatin, Chemotherapy, Ovarian Cancer, Clinical Trial, Pleural Mesothelioma, Esophageal Cancer.

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