Search

Plasma deoxycytidine levels can vary markedly during chemotherapy, from < 0.05 microM to at least 10.3 microM in T-cell acute lymphoblastic leukemia (T-ALL). This study demonstrates that clinically relevant deoxycytidine levels can dramatically protect human T-ALL cells against 9-beta-D-arabinofuranosylguanine (araG), a promising drug in this leukemia. At 0.4, 1.2, 3.6, and 10.8 microM deoxycytidine, the dose of araG required to kill 50% of MOLT3 T-ALL cells increased 4.23 +/- 1.95-(mean +/- SEM), 23.1 +/- 5.42-, 39.3 +/- 19.3-, and 67.0 +/- 11.5-fold compared to araG without deoxycytidine. Such deoxycytidine concentrations sharply reduced intracellular araG levels and blocked inhibition of DNA synthesis even in the presence of 160 and 640 microM araG. These data offer the first evidence that clinically relevant deoxycytidine levels could profoundly modulate araG toxicity in T-ALL.

We have recently reported oral and parenteral bioactivity for a new GH-releasing peptide, hexarelin. In the present study, we have examined the neuroendocrine mechanism by which hexarelin and GHRP-6, two GH-releasing peptides, mediate their actions. Although previous studies have looked at the role of growth hormone-releasing hormone (GHRH) and somatostatin in regulating the action of GHRP-6 in culture and in stressed animals, our study looked at the role of both somatostatin and GHRH in regulating the action of hexarelin as well as GHRP-6 in conscious and freely-moving, nonstressed rats. Adult male rats, prepared with indwelling jugular catheters, were pretreated i.v. with either control antiserum (CTLas), growth hormone-releasing hormone antiserum (GHRHas), somatostatin antiserum (SSas), or both GHRHas and SSas. Animals were then treated i.v. with 25 micrograms/kg of either hexarelin or GHRP-6 4 h after i.v. antisera pretreatment. Blood samples were collected every 20 min for the 3 h prior to peptide treatment and at 5, 10, 15, 20, 40 and 60 min following hexarelin or GHRP-6 injection. The peak plasma GH responses in rats pretreated with CTLas were 552 +/- 125 ng/ml following hexarelin administration and 386 +/- 132 ng/ml following GHRP-6 administration. Rats pretreated with SSas exhibited peak GH responses following hexarelin or GHRP-6 of 702 +/- 115 and 312 +/- 42 ng/ml, respectively. These plasma GH responses were similar to those observed in the CTLas-pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)