Edward E. Luck

Behavior of solubilized collagen as a bioimplant.

Abstract Pepsin-solubilized allogeneic and xenogeneic collagen has been shown in the experiments reported here to persist as a stable graft which is vascularized and colonized by host tissue cells and thus may be regarded as having formed a matrix for viable connective tissue.

The effect of intralesional 5-fluorouracil therapeutic implant (MPI 5003) for treatment of basal cell carcinoma.

BACKGROUND Basal cell carcinomas (BCCs) are usually treated with ablative procedures. A nonsurgical treatment alternative would be of value in selected patients. OBJECTIVE We evaluated the safety and efficacy of a new preparation for intralesional sustained-release chemotherapy with MPI 5003, 5-Fluorouracil Therapeutic Implant, for treatment of BCCs. METHODS Two doses of intralesional MPI 5003 (0.25 and 0.5 ml) were compared in a double-blind study of 20 patients with biopsy-proven BCC. One BCC per patient was treated weekly for up to 6 weeks and followed up monthly for 3 months until excisional biopsy for histologic examination. Before excision the cosmetic appearance of the test site was graded. RESULTS Eighty percent of 10 BCCs treated with 0.5 ml of MPI 5003 had histologically confirmed cures as compared with 60% of 10 tumors treated with the lower dose (0.25 ml). Cosmetic assessments before excision were typically good to excellent. No systemic side effects occurred. CONCLUSION Results indicate the potential of MPI 5003 for targeted local chemotherapy for BCC.

Implant delivery system: Intralesional delivery of chemotherapeutic agents for treatment of spontaneous skin tumors in veterinary patients

Abstract Anew approach to targeted drug administration using intralesional chemotherapy delivered via therapeutic implant (TI) technology was evaluated in a wide variety of spontaneously occurring skin and subcutaneous tumors in veterinary patients. Many of these animal tumors show similarities in histology and biologic behavior to human epitheliomas and neoplasms and, therefore, serve as appropriate preclinical models for human studies. These animal studies provided valuable insight into this method of local chemotherapy which is now under evaluation with 5-fluorouracil, methotrexate, and cisplatin for treatment of human skin diseases as well as cancer. Administration of free drugs directly into tumors has met with some success in the treatment of superficial lesions including keratoacanthoma, 1 basal cell carcinoma, 2,3 verruca plantaris, 4–6 condyloma acuminatum, 6–8 and Kaposis sarcoma. 9 In an effort to improve the response to local chemotherapy we used the therapeutic implant to increase the dose and duration of exposure of selected drugs to tumors, thereby maximizing the therapeutic response while minimizing toxicity to normal tissue.

Antitumor effect of intratumoral administration of fluorouracil/epinephrine injectable gel in C3H mice

Fluorouracil/epinephrine injectable gel (5-FU/epi gel) was evaluated in vitro for its drug-release profile characteristics and in a mouse tumor model for its antitumor effectiveness. In vitro chemosensitivity studies with 5-FU in RIF-1 fibrosarcoma cells showed less than 1 log cell kill at 1 mM after 2 h of exposure. Increasing the exposure time to 24 h resulted in greater cell killing (∼ 2.5 log cell kill at 0.5 mM), suggesting that sustained drug levels in tumors would result in an increased efficacy outcome in vivo. A 5-FU/epi injectable gel was designed, providing drug release in vitro of 50% by ∼ 4 h and of 80% by 24 h. The retention of 5-FU in RIF-1 mouse tumors was determined after intratumoral administration of 5-FU/epi gel or various combinations of the formulation components. Area-under-the-curve (AUC0–24 h) calculations resulted in an AUC value of 146.4% h for the 5-FU/epi gel formulation as compared with 45.7% h for 5-FU solution. Tumor growth was significantly delayed (P<0.05) with the 5=FU/epi gel (60 mg/kg) as compared with 5-FU solution given intratumorally or systemically. A fluorouracil dose of 150 mg/kg in the 5-FU/epi gel given weekly for 13 weeks was not lethally toxic, whereas the same dose given as drug solution was 100% lethal, suggesting that the therapeutic index for 5-FU in the gel formulation may be much greater than that for aqueous drug solution delivered intratumorally.

Chemosensitivity of human neoplasms with in vitro clone formation

SummaryWe analyze experience with 600 specimens for in vitro chemosensitivity assessment of human neoplasms utilizing a soft agar colony-forming technique. Good test reproducibility is demonstrated. Disaggregation with collagenase enhances yield and does not alter chemosensitivity profiles. Therapeutic exposure to chemotherapy prior to biopsy reduces in vitro sensitivity to the specific agents used in vitro. The cyclophosphamide derivatives 4-hydroperoxycyclophosphamide (4-HC) and phosphoramide mustard are active in vitro, and produce comparable rank order sensitivities among tested tumors. There is marked reduction of in vitro 4-HC sensitivity in patients with prior therapeutic cyclophosphamide exposure, supporting the use of this derivative in test systems. Rank order of test results among specimens is compared at 0.1 μg and 10 μg drug/ml. Substantial differences in rank order at these two dose levels are demonstrated, indicating that the in vitro test dose selected is an important variable.