pyrimidinones and Carcinoma--Small-Cell

Lung cancer has long been considered a disease that might benefit from the dose escalation of radio/chemotherapy afforded by a stem cell transplant. However, the clinical experience with high-dose chemotherapy and autologous bone marrow transplantation in lung cancer has been disappointing, with most trials showing little or no improvement in long-term survival. Unfortunately, lung cancer has a tendency to metastasize to the bone marrow, and lung cancer cells are known to circulate in the peripheral blood. Therefore, there is concern that autologous stem cell grafts from lung cancer patients may reinoculate recipients with live tumor cells. Photochemical purging of stem cell grafts with Merocyanine 540 (MC540) is highly effective against a wide range of leukemia and lymphoma cells and is well tolerated by normal hematopoietic stem and progenitor cells. Most solid tumor cells (including lung cancer cells), however, are only moderately sensitive or refractory to MC540-mediated photodynamic therapy (PDT). We report here that postirradiation hyperthermia (< or = 42 degrees C, 3 h) potentiates the MC540-mediated photoinactivation of both wild-type (H69) and cisplatin-resistant mutant (H69/CDDP) small cell lung cancer cells by several orders of magnitude, while only minimally enhancing the depletion of normal human granulocyte/macrophage progenitor cells. Our data suggest that postirradiation hyperthermia provides a simple and effective means of extending the utility of MC540-PDT to the purging of stem cell grafts contaminated with lung cancer and possibly other solid tumor cells.

Topics: Bone Marrow Purging; Carcinoma, Small Cell; Hematopoietic Stem Cell Transplantation; Humans; Hyperthermia, Induced; Lung Neoplasms; Photosensitizing Agents; Pyrimidinones; Transplantation, Autologous; Tumor Cells, Cultured

One limitation of autologous bone marrow transplantation for patients with cancer has been the presence of tumor cells in the bone marrow. Methods to eliminate tumor cells while preserving hematopoietic stem cells have been sought. The present study was performed to analyze the in vitro effectiveness of light-activated merocyanine 540 phototreatment (LAMP) and an aminothiol (ethiofos) as a marrow-purging regimen for small cell lung cancer (SCLC). Two human SCLC cell lines (ATCC HTB-119 and HTB-120) were treated with LAMP and exposed to light for varying periods of time up to 120 min. LAMP reduced SCLC cell proliferation and colony formation in a light exposure-dependent manner; colony formation was not totally inhibited until light exposure of 120 min was used. At this light exposure interval, multipotential hematopoietic progenitors, colony-forming units-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), were substantially reduced. In an attempt to diminish hematopoietic toxicity, SCLC cells were incubated with ethiofos (formerly WR-2721) for 1 hour before LAMP. SCLC colony formation was eliminated at light exposure intervals (90 min or less) which had no inhibitory effect on CFU-GEMM. Ethiofos did not protect CFU-GEMM from LAMP inhibition at 120 min. Ethiofos alone had no effect on the SCLC or hematopoietic cells. When normal bone marrow was contaminated with 1 or 5% SCLC cells, ethiofos plus 60 min of LAMP eliminated SCLC cells but had no effect on CFU-GEMM. The results suggest that ethiofos sensitized SCLC cells to LAMP; thus ethiofos-enhanced LAMP may be an effective method for removing metastatic SCLC cells from bone marrow used for autologous marrow transplantation after high dose chemotherapy.

Topics: Amifostine; Bone Marrow; Carcinoma, Small Cell; Cell Survival; Hematopoiesis; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Organothiophosphorus Compounds; Photochemotherapy; Pyrimidinones; Radiation-Protective Agents; Tumor Cells, Cultured