CLINICAL ?UWERSAL OF DRUG RESISTANCE Robert F. 0~01s and Peter O'Dwyer, Fox Chase Cancer Center, Philadelphia, PA, USA

Acquired drug resistance and cross resistance remains a major cause of chemotherapy failure in lung cancer and other solid tumors and is an area of intense laboratory and clinical investigation. Platinum analogs and alkylating agents are among the most widely used agents for the treatment of lung cancer Our studies have focused upon the mechanisms associated with resistance to platinum compounds and alkylating agents and upon biochemical ways which may circumvent this resistance. There are multiple mechanisms of resistance to alkylating agents and platinum compounds. Major cellular mechanisms include: alterations in drug transport; enhanced detoxification pathways [potentially direct binding with glutathione (GSH) or metallathionein and enzymatic inactivation with GSH transferases (GST)]; and increased repair of tolerance of DNA damage. Our clinical trials are focused upon GSH and GST as potential sites of modulation of resistance to platinum compounds. In addition, we intend to initiate clinical trials inhibiting DNA repair.

We have demonstrated in experimental model systems of human cancer that GSH is elevated in association with the degree of resistance to platinum and alkylating agents. Furthermore, lowering GSH levels with buthionine sulfoximine (BSO), an inhibitor of y-glutamyl cysteine synthesis (Y-GCS) restores sensitivity to alkylating agents and platinum compounds invitroand in viva. Similary, inhibition of DNA repair with aphidicolin, inhibitor of DNA polymerase, restores sensitivity to platinum compounds in relevant and model systems of human cancer.

Based on these observations we have performed a Phase I trial of BSO plus melphalan (L-PAM) in drug resistant cancer patients. Currently, 34 patients have been treated on a dose escalation study of BSO followed by L-PAM. In the first week, BSO was administered intravenously initially at the starting dose of 1500 mg/M' at 12 hour intervals for six doses. In the second week, the same schedule of BSO was followed for one hour after the fifth dose, L-PAM (15 mg/M2) was administered as a 30-minute infusion. Cycles of BSO and L-PAM were repeated at three week intervals provided white blood cell and platelet counts had recovered at pre-treatment levels. After 1.5 gm/M2 dose of BSO, prohibitive myelotoxicity lead to a dose reduction to 10 mg/M2 of L-PAM. until the 17 gm/M2 of BSO have we observed Grade 4 toxicity in this

Not

combination. A major purpose of this study was determined if GSH levels could be

decreased to about 10% of control in polymorphonuclear cells (PMN) and tumor cells. At doses above 10,500 mg/M2, all patients had depletion to approximately 10% of control in their PMN cells. Nadirs were usually observed on day 3. Tumor biopsies also show that higher but not at lower levels, a substantial effect on GSH was exerted. In addition, we have observed responses to BSO plus L-PAM in patients with ovarian and small cell lung cancer entered on this Phase I trial.

Our plan is to shortly conclude the Phase I trial and then begin a Phase II trial of the combination of BSO plus L-PAM. This will be followed by Phase I trial of BSO plus carboplatin and a Phase I trial of aphidicolin plus carboplatin. These studies suggest that biochemical modulation of factors associated with drug resistance is clinically feasible. Additional clinical trials will be necessary to determine whether modulation restores clinical sensitivity.

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O'Dwyer PJ, Hamilton TC, Young RC, LaCreta FP, Carp N, Tew KD, Padavic K, Comis RL, and 0~01s RF. Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: Clinical and biochemical results. J Nat1 Cancer Inst 84:264-261. 1992.