levoleucovorin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Solid tumors may occur in 3% of the patients with chronic myeloid leukemia (CML). Philadelphia (Ph)-positive CML was diagnosed in a 66-year-old man upon a white blood cell count of 58.1 x 10(9)/L. He had no symptoms and physical findings 3 years after treatment for rectal adenocarcinoma. Imatinib mesylate 400 mg/day was started and white blood cell count was lowered to 5.7 x 10(9)/L in 1 month. The patient had received several chemotherapeutic agents such as 5-fluorouracil, irinotecan, raltitrexed, capecitabine, and oxaliplatin. In the literature, there are two reports on CML after the treatment of colorectal carcinoma. The possibility of a relationship between oxaliplatin and/or irinotecan and CML may not be fully excluded. In conclusion, hematological disorders such as CML may emerge in colorectal carcinoma and whole blood counts should be carefully checked. The possibility of a relationship between CML and the chemotherapeutic agents in colorectal carcinoma should be further evaluated.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Fluorouracil; Fusion Proteins, bcr-abl; Humans; In Situ Hybridization, Fluorescence; Irinotecan; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver Neoplasms; Male; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Philadelphia Chromosome; Quinazolines; Rectal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Thiophenes

Acquired multifocal white retinal lesions in an immunosuppressed patient are diagnostically challenging.. Case report of a 34-year-old woman who underwent bone marrow transplantation for chronic myelogenous leukemia. Four months after the transplant, while on relatively high doses of immunosuppressive drugs, she developed bilateral multifocal retinitis versus leukemic retinal infiltration. Fine-needle aspiration biopsy was performed on one eye in an attempt to establish a cytological diagnosis.. The aspirate was found to contain individual crescent-shaped intraretinal organisms and cysts, consistent with the diagnosis of toxoplasmic retinitis. The patient was started immediately on an anti-toxoplasmosis regimen consisting of sulfadiazine, pyrimethamine, and folinic acid. Follow-up examinations revealed complete inactivation of the retinitis and no delayed complications of the biopsy.. Fine-needle aspiration biopsy can be a useful diagnostic tool in selected patients with acquired retinal infiltrates.

Topics: Adult; Antiprotozoal Agents; Biopsy, Fine-Needle; Bone Marrow Transplantation; Drug Therapy, Combination; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pyrimethamine; Retinitis; Sulfadiazine; Toxoplasmosis, Ocular; Vitreous Body

The resistance to folate-based antifolates is associated with impaired function of the reduced folate carrier (RFC), one of the major routes of folate transport into cancer cells. To clarify the importance of RFC functions in the antifolate resistance, we have examined the expression of RFC1 and its phenotype as a folate transporter in human leukemia cell lines resistant to various antifolates. MOLT-3 cells resistant to ZD9331 (a thymidylate synthase (TS) inhibitor that utilizes the RFC for cell entry) (MOLT-3/ZD9331) showed decreased expression of RFC1 concomitant with diminished cellular uptake of [3H]methotrexate (MTX). K562 cells resistant to raltitrexed (ZD1694, another TS inhibitor that utilizes the RFC for cell entry) (K562/ ZD1694 x C) scarcely expressed RFC1, which is in accordance with the impaired uptake of folate analogs and the high degree of resistance to ZD1694 and MTX. On the other hand, no apparent decrease of RFCI1 expression was found in transport-deficient MTX-resistant MOLT-3 cells (MOLT-3/MTX10000) though its phenotype showed defective transport of MTX or ZD1694. In these cell lines with impaired RFC function, [3H]leucovorin (LV) uptake was only moderately decreased as compared to [3H]MTX or [3H]ZD1694 uptake. These cells grew with a minimal retardation in folate-free medium supplemented with 10 nM LV, suggesting that these cell lines with impaired RFC function had enough folate transporters to transport LV. In contrast to downregulation of RFC, the much greater uptake of [3H]MTX was observed in the MOLT-3/trimetrexate (TMQ)800-MTX10000 in parallel with increased RFC1 expression. These cell lines with the altered expression of RFC1 may serve as models useful for investigating the regulation of RFC1 expression and for understanding the molecular mechanism(s) behind the transport-mediated antifolate resistance.

Topics: Antimetabolites, Antineoplastic; Biological Transport; Carrier Proteins; Drug Resistance, Neoplasm; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Proteins; Membrane Transport Proteins; Methotrexate; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Quinazolines; Tetrahydrofolate Dehydrogenase; Thiophenes; Tumor Cells, Cultured

The biological activities of novel analogues of methotrexate (MTX) and aminopterin (AMT) in which the gamma-carboxyl was replaced by a 1H-tetrazol-5-yl ring, an isosteric group with acidic properties similar to a carboxyl group, were investigated. The tetrazolyl analogues of MTX and AMT were more potent inhibitors of the growth of CCRF-CEM and K562 human leukemia cell lines during continuous (120 h) and 24-h pulse exposure than were the respective parent drugs; only when the exposure time was reduced to 6 h were the parent drugs more potent. These inhibitory effects on growth correlated with the onset of and recovery from inhibition of de novo thymidylate biosynthesis. Growth inhibition by the analogues was protectable by leucovorin. MTX-resistant CCRF-CEM sublines with decreased transport or increased dihydrofolate reductase (DHFR) levels were cross-resistant to the analogues. The analogues were as potent as their parent drugs in inhibiting DHFR activity in vitro and at displacing [3H]MTX from intracellular DHFR. Each analogue was more effective than its parent drug at inhibiting uptake of [3H]MTX into CCRF-CEM cells. The tetrazole analogue of AMT was a linear competitive inhibitor (Kis = 50 microM) of CCRF-CEM folylpolyglutamate synthetase, while the tetrazole analogue of MTX, unlike all other inhibitors, was linear noncompetitive (Kis = 51 microM, Kii = 321 microM). The data suggest that, compared with MTX or AMT, the tetrazole substituent, in place of the gamma-carboxyl group, allows more efficient transport into cells via the reduced folate/MTX carrier and the resulting greater uptake of the analogues leads to inhibition of DNA synthesis and cell death at lower extracellular concentrations during long exposures. The mechanism of cell death could involve inhibition at folypolyglutamate synthetase, but DHFR is the primary target. The low potency of the analogues during short exposure is presumably related to the inability to form the poly-gamma-glutamyl metabolites required for intracellular retention.

Topics: Aminopterin; Animals; Biological Transport; Cell Division; Folic Acid Antagonists; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Liver; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rats; Structure-Activity Relationship; Tumor Cells, Cultured