Regulatory science: a special update from the United States Food and Drug Administration: Preclinical issues and status of investigation of botanical drug products in the United States.

A recent survey was conducted across the therapeutic divisions within the CDER, U.S. FDA regarding the number of submissions related to botanical drug products over the past ten years. The overall number of botanical submissions as expressed in the parenthesis are as follows: 1990 (1), 1991 (4), 1992 (4), 1993 (5), 1994 (6), 1995 (5), 1996 (13), 1997 (16), 1998 (10). In the total of 64 counted, 50 of them are submitted in original IND and the rest (14) in pre-IND format. The therapeutic categories are focused on dermatological and topical (19), anti AIDS/antiviral (12), oncologic (13), neuropharmacologic (8), endocrine and metabolic (3), urologic (2), tobacco (2), and cardio-renal products (1). The regulatory actions taken on these submissions showed that 68% of them are evaluated as safe to proceed for the human trials, while the rest (32%) of submissions required agency's regulatory guidance. Among the submissions that required further guidance, 81% were deficient in preclinical pharmacology/toxicology information and the rest (19%) lacks information in other areas (chemistry, clinical protocols). Following agency's guidance, 93% of the submissions that were put on hold were allowed to proceed. In summary, a total of 94% of all the botanical INDs submitted to the agency were allowed to proceed without additional animal toxicity studies conducted. In conclusion, this survey indicates that the growing public interest in botanical supplements has prompted more formal evaluation of the efficacy/safety claims of these products.

Overexpression of CC10 modifies neoplastic potential in lung cancer cells.

CC10 is infrequently expressed in non-small cell lung cancer cell lines, despite being abundantly produced by progenitor cells for normal and neoplastic airway epithelium. We overexpressed CC10 cDNA in the non-small cell lung cancer cell line A549 to determine its effect on the neoplastic phenotype. A549 cells transfected with CC10 demonstrated a marked reduction in invasiveness that was paralleled by diminished 92-kDa and absent 72-kDa metalloproteinase activity by zymography. Western analysis revealed the near absence of the corresponding matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in the CC10-transfected cell lines, but not in the vector-transfected cell lines. The CC10-transfected cell lines also demonstrated decreased adhesiveness to fibronectin compared with the controls. CC10 expression was associated with decreased anchorage-independent growth but not with decreased anchorage-dependent growth. These data suggest that loss of CC10 may contribute to carcinogenesis, because CC10 antagonizes the neoplastic phenotype.