Correlation of retention of tumor methylmercaptopurine riboside-5'-phosphate with effectiveness in CD8F1 murine mammary tumor regression.
Treatment with a combination (PMA) of (N-phosphonacetyl)-L-aspartic acid (PALA), methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) induced partial regressions of CD8F1 murine mammary tumors and provided for tumor growth inhibition without regression of Colon 38 tumors. HPLC-nucleotide pool analysis of CD8 mammary tumors obtained at various times after treatment with PMA revealed that MMPR-5'-phosphate, which inhibits de novo purine nucleotide biosynthesis, was constant at levels of approximately 2.5 nmol/mg protein for 72 hr after treatment. In contrast, the MMPR-5'-phosphate levels of C38 tumors decreased from 24-hr levels at 1.5 nmol/mg protein with a half-time of about 24 hr. Treatment of CD8 tumor-bearing mice with iodotubercidin, a potent inhibitor of adenosine/MMPR kinase, at various times after PMA, reversed both the accumulation of high levels of MMPR-5'-phosphate and the number of partial tumor regressions. These data demonstrate that a cycle of MMPR rephosphorylation is active in the CD8 mammary tumor and suggest that this recycling of MMPR is important for the optimal effect of PMA treatment.
Nord
L D
LD
Department of Cancer Research, Catholic Medical Center, Woodhaven, NY 11421, USA.
Stolfi
R L
RL
Colofiore
J R
JR
Martin
D S
DS
D015120:6-Aminonicotinamide / Q000008:administration & dosage; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008778:Methylthioinosine / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives
D001224:Aspartic Acid; D015120:6-Aminonicotinamide; D008778:Methylthioinosine; C013195:sparfosic acid; D000255:Adenosine Triphosphate; D000248:Adenosine Kinase; D010746:Phosphonoacetic Acid