methimazole and Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

The treatment of Graves' hyperthyroidism (GD) complicated with malignancy is challenging, as anti-thyroid thionamide drugs (ATDs) and anti-cancer chemotherapy are both associated with a risk of neutropenia. Treatment with conventional ATDs, radioactive iodine (RAI) or potassium iodide (KI) was attempted in 8 patients with malignancy (34-80 years of age; 2 males and 6 females) in whom GD had been fortuitously diagnosed during a detailed systematic examination. Three patients requiring surgery were initially treated conventionally with methylmercaptoimidazole (MMI), MMI and KI or RAI (group A; one patient each). The patients became euthyroid on days 17-31 and underwent surgery on days 25-47. RAI therapy was administered to one patient after surgery. The patients were then treated with KI during chemotherapy. Five other patients who did not require surgery were initially treated with 100 mg KI monotherapy (group B). The serum free T

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Antithyroid Agents; Female; Graves Disease; Humans; Hyperthyroidism; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Neoplasms; Neutropenia; Potassium Iodide; Risk Factors; Thyroidectomy

Clinical studies have shown that interventional lowering of serum free thyroxine (FT4) may be associated with extended survival in patients with some terminal cancers. The report of success with this approach in glioblastoma multiforme caused involvement of the author (A.H.) in the prospective consultative management of 23 end-stage solid tumor patients in whom hypothyroxinemia was induced to prolong life.. Patients were self-referred or recommended by attending physicians to the author (A.H.) and had advanced cancers of the brain, ovary, lung, pancreas, salivary gland, and breast or had mesothelioma or soft-tissue sarcoma. Hypothyroxinemia was achieved in euthyroid patients by using methimazole, with the addition of 3,3',5-triiodo-L-thyronine (L-T3) to prevent hypothyroidism and suppress endogenous thyrotropin (TSH). In patients with pre-existent primary hypothyroidism, T3 administration was substituted for T4 replacement. Serum FT4 and TSH concentrations were serially monitored to enable adjustments to drug therapy and prevent clinical hypothyroidism. Survival was measured from the date of hypothyroxinemia induction with T3 or methimazole plus T3. Outcomes were compared with the odds of death based on the Surveillance Epidemiology and End Results and American Joint Committee on Cancer databases and literature reports.. The survival time of 83% (19 of 23) of patients exceeded the 20% expected 1-year survival for this hypothyroxinemic, end-stage cancer group. The difference between actual and expected survival was significant.. Although this is an uncontrolled observational experience with frank limitations, compassionate medical induction of hypothyroxinemia should be considered for patients with advanced cancers to whom other avenues of treatment are closed.

Topics: Adult; Aged; Aged, 80 and over; Diazonium Compounds; Female; Humans; Hypothyroidism; Male; Methimazole; Middle Aged; Neoplasms; Survival Analysis; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Adenocarcinoma; Adenoma; Animals; Female; Hyperplasia; Hypertrophy; Male; Methimazole; Neoplasms; Rats; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms

Topics: Antithyroid Agents; Humans; Hyperthyroidism; Long-Acting Thyroid Stimulator; Methimazole; Neoplasms; Propylthiouracil; Thyroidectomy