6-Mercaptopurine: Cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts

Bökkerink, J.P.M.; Stet, E. H.; Abreu, Ronney A. De; Damen, Frank J.M.; Hulscher, Tilly W.; Bakker, Marinka A.H.; Baal, John A. Van

doi:10.1016/0006-2952(93)90045-x

Cited by 85 publications

(73 citation statements)

References 23 publications

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“…Once the model is identified for a cancer, predictions could be made (as exemplified in this paper) on an individual basis for incoming patients. As mentioned early, the clinically related studies by Lillyman and Lennard 13 and Schmiegelow et al 22 and the in vitro work of Bo¨kkerink et al 3 hint at the positive relationship between metabolite levels, the corresponding death rates, and the resulting probability of cure. By modeling this system, the appropriate durations of treatment or treatment adjustments can be made quantitatively for individual patients.…”

Section: Discussionmentioning

confidence: 93%

“…13 High drug metabolite levels are associated with a decreased risk of relapse 22 and increased cytotoxicity in vitro. 3 To assist with the design of the optimal treatment strategies, mathematical models have been used to estimate cancer cell populations and the response to chemotherapy. To name a few, analytical approaches have been used to examine the effect on specific cellular responses such as drug resistance, 11 quiescent populations, 2,7 spatial and diffusion effects, 1,4 and cell cyclespecific drugs 5,9 for use in optimal treatment designs.…”

Section: Introductionmentioning

confidence: 99%

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Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

et al. 2007

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Abstract-The objective of chemotherapy is to eradicate all cancerous cells. However, due to the stochastic behavior of cells, the elimination of all cancerous cells must be discussed probabilistically. We hypothesize, and demonstrate in the results, that the mean and standard deviation of a cancer cell population, derived through the probabilistic interpretation of population balance equations, are sufficient to estimate the likelihood of cancer eradication. Our analysis of a binary cell division model reveals that an expected cancer population that is six standard deviations less than one cell provides a good estimate for the treatment durations that nearly ensures treatment successes. This approximation is evaluated and tested on two other physiologically likely scenarios: variable patient response to chemotherapy and the presence of a dormant population. We find that early identification of individual patient susceptibility to the chemotherapeutic agent is extremely important to all patients as treatment adjustments for non-responders greatly enhances their likelihood of cure while responders need not be subjected to needlessly harsh treatments. Presence of a dormant population increases both the required treatment duration and population variability, but the same estimation method holds. This work is a step toward using stochastic models for a quantitative evaluation of chemotherapy.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

et al. 2007

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“…15 These methylated derivatives also have an immunosuppressive effect. 22,23 TG is also methylated, to a lesser extent, in 6-methyl tioguanine through TPMT and in 6-thioxantine by guanase, and then to 6-thiouric acid through XO 24 (Figure 1). …”

Section: Discussionmentioning

confidence: 99%

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

Bonaz

Boitard

Marteau

et al. 2003

Aliment Pharmacol Ther

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Summary Background: Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases. Aims : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP. Methods : An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy. Results : Forty‐nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13–21 days after TG was started. No haematological side‐effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG. Conclusions : TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

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“…6TGN-thymidine base pairs may activate the post-replicative mismatch repair systems, and unsuccessful attempts to correct 6TGN-thymidine mispairing may lead to DNA strand breaks and other chromosome aberrations [4]. Some of the methylated 6MP metabolites, most notably methyl thioinosine monophosphate (Me-TIMP), are strong inhibitors of purine de novo synthesis [5].…”

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confidence: 99%

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Hedeland

Hvidt

Nersting

et al. 2009

Cancer Chemother Pharmacol

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Purpose To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). Methods We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy. Results DNA-6TGN levels were signiWcantly correlated to E-6TGN (r p = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/ E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r p = ¡0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r p = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. Conclusions DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

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6-Mercaptopurine: Cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts

Cited by 85 publications

References 23 publications

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

Estimation of Likely Cancer Cure Using First- and Second-Order Product Densities of Population Balance Models

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

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