levoleucovorin and Cell-Transformation--Neoplastic

The risk of malignant transformation of molar pregnancies after human chorionic gonadotropin levels return to normal is low, roughly 0.4%, but may justify an adaptation of monitoring strategies for certain patients.. This study aimed to determine the risk of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in women with molar pregnancy and identify risk factors for this type of malignant transformation to optimize follow-up protocols after human chorionic gonadotropin normalization.. This was a retrospective observational national cohort study based at the French National Center for Trophoblastic Diseases of 7761 patients, treated between 1999 and 2020 for gestational trophoblastic disease, whose human chorionic gonadotropin levels returned spontaneously to normal.. Among 7761 patients whose human chorionic gonadotropin levels returned to normal, 20 (0.26%) developed gestational trophoblastic neoplasia. The risk of malignant transformation varied with the type of mole, from 0% (0 of 2592 cases) for histologically proven partial mole to 0.36% for complete mole (18 of 5045) and 2.1% (2 of 95) for twin molar pregnancy. The median time to diagnosis of malignant transformation after human chorionic gonadotropin normalization was 11.4 months (range, 1-34 months). At diagnosis, 16 of 20 patients (80%) had the International Federation of Gynecology and Obstetrics stage I tumor, and 10 of 20 patients (50%) had a tumor classified as low risk in terms of the International Federation of Gynecology and Obstetrics score. In 9 of 20 patients (45%), the most common first-line treatment was combination chemotherapy. A quarter of these tumors (5 of 20) were histologically proven placental site or epithelioid trophoblastic tumors. In univariate analysis, the factors significantly associated with a higher risk of developing gestational trophoblastic neoplasia after the end of the normal human chorionic gonadotropin monitoring period were age of ≥45 years (odds ratio, 8.3; 95% confidence interval, 2.0-32.7; P=.004) and time to human chorionic gonadotropin normalization of ≥8 weeks (odds ratio, 7.7; 95% confidence interval, 1.1-335; P=.03). The risk was even higher for human chorionic gonadotropin normalization times of ≥17 weeks (odds ratio, 19.5; 95% confidence interval, 3.3-206; P<.001).. In this group of patients with gestational trophoblastic disease, none of the those with pathologically verified partial mole had malignant transformation, supporting the current recommendation of stopping human chorionic gonadotropin monitoring after 3 successive negative tests. In cases of complete mole or twin molar pregnancy, we proposed to extend the monitoring period with quarterly human chorionic gonadotropin measurements for an additional 30 months in patients with the identified risk factors for late malignant transformation (age, ≥45 years; time to human chorionic gonadotropin normalization, ≥8 weeks).

Topics: Adolescent; Adult; Aftercare; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Transformation, Neoplastic; Choriocarcinoma; Chorionic Gonadotropin; Cisplatin; Cyclophosphamide; Dactinomycin; Etoposide; Female; France; Gestational Trophoblastic Disease; Humans; Hydatidiform Mole; Hysterectomy; Leucovorin; Methotrexate; Middle Aged; Neoplasm Staging; Pregnancy; Retrospective Studies; Trophoblastic Tumor, Placental Site; Uterine Neoplasms; Vincristine; Young Adult

Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Artifacts; Biological Transport; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dideoxynucleosides; Diffusion Magnetic Resonance Imaging; Female; Fluorouracil; HCT116 Cells; Humans; Leucovorin; Mice; Organoplatinum Compounds; Thymidine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Transformation, Neoplastic; Cyclophosphamide; Diabetes Mellitus; Doxorubicin; Humans; Hypertriglyceridemia; Insulin Resistance; Leucovorin; Lipodystrophy; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Mycosis Fungoides; Parotid Diseases; Parotid Gland; Prednisone; Skin Neoplasms; Vincristine

Three sublines of NIH 3T3 cells had the properties of non-neoplastic, preneoplastic, and neoplastic cells, respectively. The closer the cells were to neoplastic behavior, characterized by continuing growth at high density, the slower they multiplied at lower density. Under the conditions of high population density and low calf serum concentration used in the assay for transformed focus formation, the transformed or neoplastic cells were much more sensitive to killing by methotrexate (MTX) than were non-neoplastic cells in the same culture. This differential sensitivity of neoplastic cells was far more pronounced in molecular, cellular, and developmental biology medium 402 (MCDB 402) than in DMEM. It is associated with the presence in MCDB 402 of folinic acid, known clinically as leucovorin, which is a reduced form of the folic acid present in DMEM. Although leucovorin had been shown to selectively spare normal bone marrow and intestine in animals from the killing effect of MTX on tumor cells, we demonstrate the preferential killing of neoplastic over non-neoplastic cells of the same derivation. Neither neoplastic nor non-neoplastic cells were killed once they had stopped multiplying at their respective saturation densities. The development of the light foci characteristic of the preneoplastic cells was less sensitive to MTX than the formation of the dense foci produced by the fully neoplastic cells. The system should serve as a valuable model to establish basic principles and optimal conditions for selective killing of neoplastic cells by chemotherapeutic drugs.

Topics: 3T3 Cells; Animals; Cell Division; Cell Survival; Cell Transformation, Neoplastic; Culture Media; Kinetics; Leucovorin; Methotrexate; Mice; Neoplasms, Experimental; Precancerous Conditions; Time Factors

Cultures of Friend erythroleukemia cells were subjected to the antibiotics trimethoprim (T) and sulfamethoxazole (S) at levels equal to or below the usual therapeutic range. At T 8 microgram/ml and S 40 microgram/ml, cell growth was arrested, cells appeared megaloblastic, and the examination of cell-cycle distribution by flow microfluorimetry revealed arrest in S phase. With a tenfold reduction in drug levels (T, 08 microgram/ml; S, 4 microgram/ml) cell growth was less markedly inhibited, morphology remained megaloblastic, and S-phase block was still dramatic. A further tenfold reduction (T, 0.08 microgram/ml; S, 0.4 microgram/ml), well below effective antibacterial levels, allowed normal cell growth and morphology but DNA synthesis was still inhibited. Additions of folinic acid at 100 ng/ml averted all drug effects. Thus T/S can affect cell replication even at levels well below those usually employed and could prolong the rate of recovery of hematopoietic cells in the myelosuppressed patient.

Topics: Cell Transformation, Neoplastic; Cells, Cultured; DNA; Dose-Response Relationship, Drug; Erythrocyte Volume; Friend murine leukemia virus; Leucovorin; Leukemia, Erythroblastic, Acute; Megaloblasts; Sulfamethoxazole; Trimethoprim

The role of folate metabolism in growth control in monolayer and suspension cell cultures was studied in three related cell lines: BHK-21, polyoma-transformed BHK-21 (PyBHK), and an aminopterin-resistant derivative of BHK-21 (A5). BHK-21 cells had extremely low levels of dihydrofolate reductase, PyBHK had higher levels, and A5 had extremely high levels. Hypoxanthine and thymidine together, but not individually, induced BHK-21 to grow in agar, and stimulated its growth in agarose and monolayer culture. PyBHK and A5 grew spontaneously in agar, and hypoxanthine plus thymidine had little or no effect on their growth either in suspension or in monolayer cultures. We found that exogenous folinic acid, a derivative of folate metabolism that bypasses the function of dihydrofolate reductase, mimicked the growth-stimulatory effects of exogenous hypoxanthine plus thymidine BHK-21. We conclude that the growth limitation of BHK-21 in suspension culture is due, in part, to a deficiency of dihydrofolate reductase. This enzyme deficiency limits nucleoside synthesis and can be overcome by supplying end products of this pathway.

Topics: Aminopterin; Animals; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cricetinae; Drug Resistance; Folic Acid; Hypoxanthines; Kidney; Leucovorin; Tetrahydrofolate Dehydrogenase; Thymidine

Normal and Rous sarcoma virus-infected chicken fibroblasts proliferate maximally in a culture medium containing a physiological (10 ng/ml) concentration of 5-methyltetrahydrofolic acid or folinic acid (5-formyltetrahydrofolic acid), while their maximal proliferation requires a hyperphysiological (1000 ng/ml) concentration of folic acid. The normal and Rous-infected fibroblasts do not differ in their requirements for 5-methyltetrahydrofolate, folinic acid, or folic acid.

Topics: Animals; Avian Sarcoma Viruses; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Chickens; Culture Media; Leucovorin; Tetrahydrofolates