To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.

https://www.nejm.org/doi/pdf/10.1056/NEJM198011203032101?listPDF=true

Streptozocin Alone Compared with Streptozocin plus Fluorouracil in the Treatment of Advanced Islet-Cell Carcinoma

An Odyssey in the Land of Small Tumors

The pancreatic islet is composed of three types of cells of neural crest origin, each with distinct histochemical and electromicroscopic features. Each type of cell may give rise to a beni...

Islet Cell Tumors: Current Concepts and Management

The mouse, dog, and monkey toxicity data on 30 drugs was retrospectively analyzed in comparison with the actual clinical dose schedules used in man. Animal dose schedules were converted to the human schedule and comparisons were made of the human dose versus the large animal toxic dose low, toxic dose high, and lethal dose, the lethal doses for 10% and 90% of normal mice, and the optimal dose in tumor-bearing mice. If the starting dose in Phase 1 clinical trials had been selected by calculating one-third of the toxic dose low (in mg/sq m) in the most sensitive large animal species, 5 of the 30 drugs would have produced significant toxicity in the first patient. The lethal doses for 10 and 90% of normal mice and the optimal dose in L1210-bearing mice were found to offer good quantitative prediction of human toxicity. Determination of a safe and practical starting dose for Phase 1 studies should take into account not only dog and monkey data but also toxicology data in normal and tumor-bearing mice.

https://cancerres.aacrjournals.org/content/canres/35/5/1354.full.pdf

Quantitative Prediction of Drug Toxicity in Humans from Toxicology in Small and Large Animals

Thyroid hormones take major part in normal growth, development and metabolism. Over a century of research has supported a relationship between thyroid hormones and the pathophysiology of various cancer types. In vitro studies as well as research in animal models demonstrated an effect of the thyroid hormones T3 and T4 on cancer proliferation, apoptosis, invasiveness and angiogenesis. Thyroid hormones mediate their effects on the cancer cell through several non-genomic pathways including activation of the plasma membrane receptor integrin αvβ3. Furthermore, cancer development and progression are affected by dysregulation of local bioavailability of thyroid hormones. Case-control and population-based studies provide conflicting results regarding the association between thyroid hormones and cancer. However, a large body of evidence suggests that subclinical and clinical hyperthyroidism increase the risk of several solid malignancies while hypothyroidism may reduce aggressiveness or delay the onset of cancer. Additional support is provided from studies in which dysregulation of the thyroid hormone axis secondary to cancer treatment or thyroid hormone supplementation was shown to affect cancer outcomes. Recent preclinical and clinical studies in various cancer types have further shown promising outcomes following chemical reduction of thyroid hormones or inhibition or their binding to the integrin receptor. This review provides a comprehensive overview of the preclinical and clinical research conducted so far.

/pdf/thyroid-hormones-and-cancer-a-comprehensive-review-of-3a3xkmjvjv.pdf

Thyroid Hormones and Cancer: A Comprehensive Review of Preclinical and Clinical Studies

Summary Tubercidin (NSC 56408), a cytotoxic antibiotic, was used in the treatment of 93 patients with various types of advanced neoplastic disease in a Phase I study to determine human toxicity Significant toxicity was limited to the observation of nephrotoxicity in 18 cases and local irritation of veins in 12 Tumor response was suggested in only 3 cases, all of which were cases of primary carcinoma of the pancreas

/pdf/clinical-studies-with-tubercidin-administered-by-direct-j3tb1wpcbv.pdf

Clinical Studies with Tubercidin Administered by Direct Intravenous Injection

4440 Anecdotal reports and recent data suggest that decreased thyroid function may be associated with improved outcomes in lung and other solid tumors.Recently in a large population based study of patients treated for hyperthyroidism by radio-iodine ablation of the thyroid, long term follow up showed a signicantly lower prevalence and risk of dying from lung cancer .L-thyroxine [T4] which is commonly supplemented in hypothyroidism may,however, not correct intracellular hypothyroidism in tissues such as lung or restore blood IGF-1 to euthyroid levels . There is evidence too that tri-iodothyronine [T3] is a significant tumor mitogen, upregulates cyclin D1, E and modulates the IGF-1 and EGF-R growth factor systems. This multicenter study was aimed at determining the prognostic value of primary hypothyroidism on survival in lung cancer. METHODS: A hospital-based retrospective case-control study was conducted on 1979 patients with AJCC stages 1- 4 non -small cell and small cell lung cancer treated between January 1996 and July 2002. Patients with a clinical diagnosis of hypothyroidism based on documentation of thyroid hormone supplementation were individually matched to controls based on cancer histology, stage of disease, age, race, and gender. Kaplan-Meier survival curves were generated for each group. Age of cancer diagnosis for the 85 hypothyroid patients and the 1372 euthyroid patients before matching was compared. RESULTS: Overall, 85 hypothyroid cases[4.2%] and 85 matched controls were identified of which 70 were non-small cell and 15 small cell types The female: male ratio was 3.35:1. Primary tumor stage was Stage 1 :- 19 patients, Stage 2 :- 19 patients, Stage 3 :- 86 patients, and Stage 4 :- 46 patients.For AJCC stages 1-4 median survival [M.S.] was 14.5 months in the hypothyroid group and 11.1 months in the euthyroid group( p = .014) . For stage 4, M.S. was 11 vs.5 months(p= .0018). . Median age at diagnosis was 73 for hypothyroid vs. 64 years for euthyroid patients (p = .0006). CONCLUSION:This retrospective case control study suggests that primary hypothyroidism is prognostically significant and associated with a more indolent course in lung cancer.

James H. Mason

Papers

Clinical Studies with Tubercidin Administered by Direct Intravenous Injection

Thyroid hormones and lung cancer: Primary hypothyroidism is prognostically significant for survival in lung cancer