We and others have described enhanced angiogenesis in hematopoietic malignancies such as non-Hodgkin's lymphoma (NHL), myeloma, ALL, AML and MDS. In NHL, angiogenesis increases with pathological progression, and microvessel density seems higher in high-grade compared to low-grade NHL. VEGF and b-FGF, crucial angiogenic growth factors, are strong and independent prognostic factors in NHL. In addition, we found that VEGF deprivation inhibits NHL and leukemia cell lines. The Folkman group recently demonstrated in murine models of subcutaneous (sc) lung carcinoma and leukemia (Cancer Res 2000;60:1878) that "metronomic" cyclophosphamide (CTX) administration avoids drug resistance and eradicate established diseases more effectively than conventional maximum tolerable dose (MTD). Each dose of the metronomic CTX schedule induced apoptosis of tumor-associated endothelial cells (EC), and EC apoptosis preceded the apoptosis of (otherwise) drug-resistant tumor cells. We evaluated metronomic CTX in models of human high-grade NHL recently generated in our laboratory (Blood 2000;96:282). NOD/SCID mice (n=6 per group) were transplanted intraperitoneally (ip) instead of sc with NHL cells and randomly assigned on day 2 to receive metronomic (150 mg/Kg every 6 days for 6 cycles) or MTD CTX. To define MTD, mice received CTX every other day for 3 doses every 21 days. At 150 mg/Kg CTX, 60% of animals died of toxicity. At 75 mg/Kg, there was no lethal toxicity and delay of tumor growth was similar to the higher dose. Mice were transplanted with Namalwa or Granta 519 cells, the most aggressive NHL cell lines in our panel. Namalwa cells derive from a Burkitt NHL, Granta cells have a t( 11 ; 14) and overexpress cyclin D l. In mice given MTD CTX, tumor growth was delayed in comparison to untreated controls. However, on day 10-20 tumors were observed in all MTD-treated animals, and a second course of MTD CTX did not reduce tumor growth. Control and MTD-treated mice were sacrificed when tumor burdens exceeded 2,000 mm3, ie on day 35 (Namalwa) or 50 (Granta). In sharp contrast, tumor growth was not observed in mice given 6 cycles of metronomic CTX. In Namalwa mice, tumor growth was observed on day 42-48, ie one week after discontinuation of metronomic CTX. Conversely, Granta mice are still tumor-free 90 days after transplant. Untransplanted mice given metronomic CTX to assess toxicity are alive and well after day 120. In conclusion, preclinical NHL models indicate that a CTX schedule tailored to induce EC apoptosis has low toxicity and is more effective than MTD.
|Issue number||11 PART II|
|Publication status||Published - 2000|
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