**Core Concept**
Methotrexate is a chemotherapeutic agent that inhibits dihydrofolate reductase (DHFR), leading to decreased DNA synthesis and cell death. To prevent methotrexate toxicity, it is essential to counteract its effects on folate metabolism.

**Why the Correct Answer is Right**
Calcium leucovorin, also known as folinic acid, is a form of vitamin B9 that can bypass the DHFR inhibition caused by methotrexate. It acts as a rescue agent by providing an alternative route for thymidylate synthesis, thereby preventing the depletion of thymidine and other nucleotides. This mechanism helps to mitigate the toxic effects of methotrexate on rapidly dividing cells, such as bone marrow and gastrointestinal mucosa.

**Why Each Wrong Option is Incorrect**
**Option A:** MESNA (sodium 2-mercaptoethanesulfonate) is used to prevent ifosfamide-induced hemorrhagic cystitis, not methotrexate toxicity. It works by scavenging urotoxic metabolites of ifosfamide.

**Option B:** Flumazenil is a benzodiazepine receptor antagonist used to reverse benzodiazepine overdose, not methotrexate toxicity. It has no role in folate metabolism or DHFR inhibition.

**Option C:** Fomepizole is a competitive inhibitor of alcohol dehydrogenase, used to treat ethylene glycol or methanol poisoning, not methotrexate toxicity. It has no relation to folate metabolism or DHFR inhibition.

**Clinical Pearl / High-Yield Fact**
When administering methotrexate, it is crucial to monitor for signs of toxicity, such as myelosuppression, mucositis, and gastrointestinal symptoms. Calcium leucovorin should be given promptly to prevent or treat these adverse effects, especially in high-risk patients or when methotrexate doses exceed 200mg/m^2.

**✓ Correct Answer: D. Calcium leucovorin**