[New antitumor antimetabolites--gemcitabine and DMDC]

Area of Science:

• Oncology
• Pharmacology
• Cancer Research

Background:

• Gemcitabine (dFdC) and DMDC are novel antimetabolites with demonstrated antitumor activity.
• Structurally related to cytarabine (Ara-C), gemcitabine targets DNA synthesis inhibition.
• While Ara-C is effective against adult acute leukemia, solid tumors often show resistance.

Purpose of the Study:

• To evaluate the antitumor activity and safety of gemcitabine (dFdC).
• To assess gemcitabine's efficacy across a range of solid tumors.
• To compare gemcitabine's mechanism and therapeutic potential with cytarabine.

Main Methods:

• Phase I trials determined maximum-tolerated doses (MTD) for gemcitabine at various infusion schedules.
• Phase II trials evaluated gemcitabine's response rates in patients with breast, ovarian, renal, colorectal, pancreas, head and neck, and lung cancers.
• Biochemical analysis identified gemcitabine's mechanism as inhibition of ribonucleoside diphosphate reductase and DNA synthesis.

Main Results:

• Gemcitabine demonstrated antitumor activity against human leukemic cell lines and solid tumors.
• Phase I trials established MTDs ranging from 790 mg/m2 to 4,800 mg/m2 depending on infusion duration.
• Phase II trials in solid tumors, including lung and breast cancer, showed good responses with generally mild toxicities like myelosuppression and fatigue.

Conclusions:

• Gemcitabine (dFdC) exhibits significant therapeutic activity against a variety of solid tumors.
• The drug's mechanism, involving DNA synthesis inhibition and a longer half-life of its active metabolite (dFdCTP), contributes to its efficacy.
• Gemcitabine represents a promising antimetabolite for treating diverse solid malignancies.