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Way JL, Leung P, Sylvester DM

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mechanism unexplained Relative contributions of direct peptide effects versus downstream IGF-1 actions inadequately characterized Long-term receptor sensitivity and potential for desensitization inadequately studied Individual patient variability in response not well-characterized Potential for differential effects based on endogenous growth hormone status unclear Long-Term Safety Considerations Critical safety questions remain unanswered regarding chronic peptide administration: Cardiovascular safety concerns FDA warnings cite risks of increased heart rate, systemic vasodilation, flushing, and transient hypotension Immunogenicity risks FDA identifies both peptides as potentially immunogenic with risk of serious immune reactions including anaphylaxis Cancer risk theoretical concern that chronic growth hormone/IGF-1 elevation could promote cellular proliferation

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When in combination, MTX was given 6 hours before ATO (based on Szymanska et al (44), who used this interval for other drug combinations)