Lack of in vitro-in vivo correlation of a novel investigational anticancer agent, SH 30.
In solid tumors, the reasons for the lack of in vitro and in vivo correlation of drug activities are multifold and includes permeability to the tumor cells, interstitial hypertension and metabolic degradation. So, it is important to study the permeability and metabolic disposition of new compounds early in discovery and development of anticancer drugs. An experimental anti-cancer drug, SH 30 demonstrated highly selective and potent cytotoxic activity against a number of multi-drug resistant tumor cell lines in vitro. However, it was inactive in a murine tumor model. This study was conducted to identify the barriers that result in lack of correlation between in vitro and in vivo cytotoxic activity of novel anticancer agents. Two important barriers: physical (permeability) and metabolic (enzymatic inactivation) to poor delivery of SH 30 to solid tumors were investigated in this study. Tumors were sliced to separate the vascular and avascular sections. The concentrations of the drug at various regions of the tumor after single and multiple doses were investigated to determine the permeability barrier. The permeability barrier was also probed using two in vitro model systems, namely, matrigel films representing extracellular matrix and caco-2 multilayer cell cultures that simulate solid tumors. The drug and its metabolite concentrations were determined in the plasma and tumors to determine the metabolic barrier to the drug cytotoxic action. The metabolic barrier was further probed using in vitro mouse hepatocytes and liver microsome preparations. Our examination revealed the metabolic barrier to be the major contributor to the ineffectiveness of SH 30 in vivo. Examination of concentration of the drug across various regions of the tumor corroborated by data from in vitro permeation studies suggested that, for SH 30, permeability barrier did not exist. After single injection, the concentrations of SH 30 and its metabolites in plasma and tumor were comparable to another investigational drug with similar features (XK 469). Contrary to day 1, after 8 consecutive days of administration, SH 30 concentrations were significantly lower, while the metabolites concentrations were higher, suggesting extensive metabolism due to induction of enzyme(s). The in vitro hepatocytes and liver microsome results also showed SH 30 biotransformation to the same metabolites. Neither drug penetration, nor drug distribution into regions of the tumors distal to vasculature were impeded. The inactivity of SH 30 in vivo is primarily due to induction of extensive metabolism to inactive metabolites. This metabolism prevents adequate drug levels being achieved in the tumor.
Poondru
Srinivasu
S
Department of Internal Medicine, Wayne State University, MI, USA.
Parchment
Ralph E
RE
Purohit
Vivek
V
LoRusso
Patricia
P
Horwitz
Jerome P
JP
Hazeldine
Stuart T
ST
Polin
Lisa
L
Corbett
Thomas
T
Jasti
Bhaskara R
BR
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018938:Caco-2 Cells; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010539:Permeability; D011810:Quinoxalines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C465838:NSC-697887; D011810:Quinoxalines; C118180:XK 469